化學生物學概論128.講座01.引言/什麼是化學生物學？ (Introduction to Chemical Biology 128. Lecture 01. Introduction/What is Chemical Biology?)

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>> I'm going to run the class as follows.
I'll have the most important announcements
at the very beginning of the class.
So I'll be talking about stuff like, what's covered
on the midterm, what's expected
from your proposal assignment et cetera at the very beginning.
So, you definitely want to show up on time,
show up early get a sit,
be prepare because most important stuff is going to be
in that first five minutes.
OK. Oh, and by the way, feel free to interrupt
if you have any questions.
OK. So, don't hesitate to interrupt if anything comes up.
OK. So some announcements today, and again,
announcements will come
out at the very beginning of each class.
Our reading assignments this week,
I like you to obtain a textbook, it's available on the bookstore,
there are big stack of them when I visited last week.
>> They ran out.
>> They ran out?
Oh, well it's good.
OK. If they ran out, Amazon.com has them on sale
and you can get them delivered very quickly.
OK. And I know for while, Amazon was selling them
at some ridiculous discount, so.
I know because as one of the co-authors, I'm very interested
in how they're selling.
Along those lines, as one of the co-authors, I'm planning
to donate the profits of the book to anyone
in this classroom back to UCI for--
to support research in chemistry.
OK. So, I'm requiring a book that I wrote.
I'm obviously aware that I'm going to profit from that.
The profits will go back to UC Irvine.
OK. So if you have a copy of the course reader
from previous years, please throw it away.
OK. It's not going to be any good.
I mean it's good, but I've changed the material quite a bit
and the textbook is significantly improved,
the problems are slightly different.
I think it's-- the figures are much better, et cetera.
And of course it was edited.
So, the course reader
for previous years is not going to carry you.
You need to buy a copy of the textbook.
So, Natalie how does the sound sound?
>> It sounds great and I'm sorry.
Just one quick announcement.
I know this is [inaudible] tiny words could be difficult.
So, we can just work on not having to come back here
since I had like 10 minutes to set up.
And just go through the classroom on that side,
it would be it would super helpful [inaudible].
The benefit is though to you
that probably [inaudible] lecture.
All of these lectures will be available in YouTube.
>> Cool.
>> So, if you can bear with all my equipment then you can watch
these and enjoy them as many times you want.
>> Thank you Nathalie.
Yeah. So, yes, they will be posted online for you.
So, you can enjoy them and study from them et cetera.
The goal here is that you UC Irvine is one
of the very first Universities to have both lecture class
and the laboratory class in chemical biology.
We started these back in 2000
when I was an assistant professor.
And since that time, we've obviously built up quite a bit
in terms of our sophistication of presenting the subject.
And so my goal is to really bring that level
to other universities around the world and around the country.
So, any that's why we're doing this.
But it also has some benefits to you as well.
OK. So reading assignment for the first week.
Read Chapter 1.
I'm going to be covering all the material in Chapter 1
so there's nothing for you to skim through
or anything like that.
On future chapters, there will be stuff
that I won't be covering and I'll tell you when that happens.
OK. And you'll notice when it happens.
OK. If you want to get a head, start reading Chapter 2.
Chapter 1 is pretty basic.
Chapter 2 then starts getting more advanced.
Homework. Do the problems in Chapter 1,
all of the odd problems and also all of the asterisked problems
and let me add that do this.
So, all the problems that have an asterisk are--
the answers to all the problems
with an asterisk are available online.
So, I'd like you to do those as well.
OK. And then in addition, we'll be posting a worksheet,
number 1, on the website.
It's not there yet but it'll be posted very-- oh, it is there?
>> Well, it'll be this afternoon.
>> It'll be posted afterwards.
OK. So, we'll be posting that.
That will form the basis for the discussion sections.
Please work the worksheet as well.
OK. So, before I get started, before I delve
through very much more.
I want to tell you what you should be paying
attention towards.
The first thing are these announcements
that I'm giving you.
What's discussed in lecture?
The discussions that I give you in lecture are your guide
to what I think it's important.
OK. So, right before the midterm, you're going to want
to know, what do I need to know on the midterm
to get an A in this class?
And my answer is always the same which is,
what did I talked about in lecture?
What I talk about in lecture is what I think is important.
I have a limited amount of time for these lectures.
I'll be doing two lectures per chapter
of an hour and 20 minutes each.
And so, if I talk about it in lecture,
I'm telling you I think this is important.
This is something you need to know for the midterm.
OK. So, what's discussed in lecture is super important.
This includes both slides and anything else that's posted
to the website, discussion worksheets
and then the discussion in discussion as well.
If you're sitting on the left side of the classroom,
can I ask you to sort of scooch
in if you have an empty chair on your right.
So, just to create some more extra chairs
because we have people that are arriving late.
So, just sort of scooch over please.
Thank you.
OK. The next most important thing is assigned reading.
But filter the assigned reading through the filter,
through the lens of what I talk about in class.
If I talk about it in class that's telling you it's
important, if I don't talked about it, less important.
And then finally, the problems
in the textbooks as least important.
Good news, there's a few things
that you don't have to worry about.
The first of these are references on the slides.
I find it almost impossible to do stuff
without having some referral back to the literature.
That's sort of the nature of scholarship
and it totally impossible to get me to stop doing this.
When Dave and I wrote the textbook, for example,
we had a list of references that's like 10 times longer
than the one that's posted to the website.
And we found it totally impossible,
the publisher told us to stop doing it,
to leave out those references.
And so, references are basically the currency
that underpins what I'm telling you.
But on the other hand, this is an introductory class.
So, don't get worried about those.
OK. If you take a graduate class and they have references
on slides, you'll want to look up those references.
But on an undergraduate level don't get worked up about it.
OK. So, don't stress about those.
In addition, don't stress about stuff that's covered
in the textbook that we don't discuss in class.
OK. So if I, you know, I've said this before.
If I don't discuss it class and it's
in the textbook, don't worry about it.
OK. So, the text is written as sort
of an advanced undergraduate early graduate level.
And there's material there that's frankly graduate level.
But I don't want you to get stressed out about it.
OK. So, if don't talk about it in class, that's my signal
that I don't think it's so important for you to learn.
OK. Any question about what I'm telling you?
Hey.
>> Are there any textbooks reserved in the library?
>> That's a good question.
What is your name?
>> David.
>> David. Mariam, could you look into that for David?
>> I know there're not yet but they are ordering them.
So as soon as they got them--
it should be within the next two weeks.
>> OK. So, they'll be--
eventually they'll appear there but not yet.
>> Thank you
>> OK. Thanks for asking.
Other question?
What is your name?
[ Inaudible Remark ]
No, so we will not be collecting the problem sets.
We'll have plenty of other chances to learn
about your intelligence and creativity.
So another question?
>> Will the slides be posted ahead of time or--
>> Slides will be posted-- that's a good question.
I'll try. But I'm usually frantically getting ready
the day.
So I'll do my best.
Certainly the Thursday lecture will be.
But maybe not the Tuesday.
I'll do my very best though.
Other questions?
OK. More background.
Course instructors, I'm Professor Weiss.
I've been teaching this class for about 12 years.
And I absolutely love chemical biology.
It's what makes me run to work.
It is my sole passion in life.
That's a little bit of an exaggeration, but close.
OK. So what else would you like to know about me?
Here's your chance.
For the next five minutes you can ask anything you want,
personal, not so personal.
Go ahead in the back first.
So, my laboratory is at the interface
of chemistry and biology.
And we're trying to develop new ways of looking
at individual molecules
and dissecting how membrane proteins work.
Thanks for asking.
And a question over here?
[ Inaudible Remark ]
It was. I'm kind of a competitive guy.
I like driving fast I like racing.
So, yeah. Question over here?
>> What's difference between biochemistry
and chemical biology?
>> Chemical biology emphasize-- so, this is a great questions.
So, the question was what is the difference
between biochemistry and chemical biology?
Chemical biology emphasizes what's happening
at the level of atoms and bonds.
And biochemistry emphasizes what's happening
at a larger scale.
So, in biochemistry, my colleagues are content to look
at proteins as sort of large molecules
without getting too worked up about hydrogen bond here
and hydrogen bond there.
Sometimes they get worked up about those things.
But most of the time, the diagram--
signal transduction diagrams and things
like that are just large blobs.
And in this class, we'll be zooming in and looking
at the actual atoms and bonds.
OK, good question.
OK. Anything else personal?
This is your last chance, ask me anything personal.
Ask me about my pets, my hobbies, oh, go ahead.
[ Inaudible Remak ]
No, I wish I did.
I only get to go out once a year.
It's kind of the limitation.
So thanks for asking.
OK. Well, I should also let you know I have two cats.
I'm married and that's it for the personal information.
OK. OK. Last question, go ahead.
>> How many kids you have?
>> I have zero kids.
That's why I have a two-sitter car.
[ Laughter ]
OK. You guys, that's it on the personal stuff, enough about me.
I'm very pleased that this quarter,
we have really the very best TAs in the chemistry department.
I've gone through and I've handpicked TAs,
Mariam Ifftikhar is a great examplist.
Mariam and I taught this class last year
and she knows everything there is to know about this topic.
Her research is in chemical biology
and she's absolutely superb.
If she tells you something about the class, you could take
that as good as coming from me.
OK. In addition, our second TA, Krithika Mohan isn't here today.
She's been tied up in India.
But she'll be back in the next week or so.
And she's also a great source of information.
She's also a graduate student in my laboratory.
OK. So, we're lucky to have California's finest natural
resource TAing for us, Krithika and Mariam.
OK. So, in terms of office hours,
I will be having two office hours a week,
my Thursday office hours is set.
My Wednesday office hour, however, will float.
OK. So, I will always have office hours Thursday,
11 to noon.
This other office hour, the second office hour will float,
meaning that my schedule is constantly changing.
And so I'll have to change this around.
OK. So, every week, I will announce
when that office hour will take place.
If for example, my office hours don't fit your schedule,
tell me at the beginning of the week when you
like my officer hour to be.
And I'll do my best to accommodate as many people
as possibly each week.
OK. So, first office hour fixed, second office hour floating.
I will always have the office hours set up in away that's
at the interfaces between classes.
So, you don't have to attend the whole office hour,
if you can attend just the first 15 minutes or so or 10 minutes
and then fly off to your class, that's perfectly OK.
Show up for five minutes, get your question answered
and then disappear, I don't care, I don't mind.
But I'll always set them up so they're kind of at the junction
between classes that way then it's less likely
that you'll be able to tell me that you have a schedule
in conflict with everyone in my office hours.
I've heard that before and I usually ask those people
to show me their schedule classes.
And I've never seen it actually that way,
especially since I've the second office hour floating.
So there's going to be plenty of time
for you to meet this quarter.
And in fact I really want to get to know you.
OK. I will get to know the names
of 95 percent of you in this room.
I will know something about what your career aspirations are.
I will know something about your creativity in terms
of your ability to come up with noble ideas,
your writing ability, and a lot of other characteristic as well.
So, at the end of this, I will be able
to write a very good letter of recommendation for you.
OK. This is not [inaudible] the last topic, but I would like you
to shutoff your cellphones please.
OK. And that also includes text messaging as well.
Thank you.
OK. So anyway, come out to my office hours especially
in the first couple of weeks, introduce yourself.
Tell me why it is you're taking this class.
What it is you hope you learn?
What it is that you're hoping
to do once you graduate from UC Irvine.
And if there's anything I can do to help you
in that course, I will do it.
OK. That's one of my jobs.
And furthermore, even after you graduate from this class,
you can still keep in touch with me.
You can still get letters of recommendation from me
and you could still have my support
in your career aspirations.
OK. That's my promise and commitment to you.
OK. And the TAs will also have office hours each week.
Their office hours were always be on different days
and times than my office hour.
And their office hours are much more fixed than my office hour.
OK. So, any questions about anything I've said any
of the announcements so far?
OK. All right.
Textbook, I've already mentioned this.
Again, it's available on Amazon.
I understand it's sold out.
But you can get it again from Amazon.
Supplemental text, I'd like you
to have available an organic chemistry supplemental text.
When I talk about peptides, for example,
and I talk about amide bonds, I'm going to assume
that you've read the chapter on amide bonds and peptides
in this supplemental text, even if it wasn't covered in 51C.
OK. I'll just ask you to go back and read that chapter.
OK. And so you need some sort of supplemental text available
in organic chemistry as basically as reference.
OK. And it's nice because this will provide kind
of a lower key treatment of a more complex topic.
So, for example, if you want to learn the sort
of the very fundamentals of DNA or carbohydrate chemistry,
the best place to start is whatever textbook you use
for 51C.
Now, I realize, many of you sold your textbook right
after the class was over.
That was a huge mistake.
But it's not too late to change things.
Number one, I can give you or loan you a supplemental text
if necessary come to my office hours.
First five people that show up will get one of those.
Second, the library--
the science library has about three shelves that are
like this wide that are filled with organic chemistry text.
The exact text does not matter.
OK. Basically, if you look
at sophomore organic chemistry textbooks,
they're all more or less the same.
OK. What really matters through is that you have one available
to you that you can refer to as reference.
You need that for this class, OK, because I'm going to assume
that you know the material there.
Now along those lines, I've gotten a couple of emails
from some of you who are concerned.
You had trouble with 51C.
You had trouble with sophomore organic chemistry.
And now you're taking this sort
of advanced organic chemistry class and you're worried.
OK. Here's what I want you to do.
First, don't panic.
OK. I will do my best to get you up to speed on arrow pushing
and some other fundamental comment--
fundamental principles in the next two weeks.
OK. So don't panic yet.
At the end of that two weeks, if what I'm doing on the board
and your ability to keep up in discussion section
and on the homework or just, you know, apples and oranges.
You know, fields apart, OK,
you're even on the same race track,
then you can start panicking.
But for now, no panicking.
OK. If you're really,
really weak in sophomore organic chemistry, I'd like you
to open the chapters on carbonyl chemistry.
Whatever books it is, read the chapter--
re-read the chapters on carbonyl chemistry
and get up to speed on those.
If you understand how carbonyl chemist-- how carbonyls react,
how the alpha carbon is acidic and a few other things,
you'll be fine in this class.
OK. Turns out that's like 60 or 70 percent
of the organic chemistry
that underlies biology involves carbonyls.
OK. Start there first.
After you finish with the carbonyls, come see me again
and I'll get you up-- I'll give you the next topic
which will probably be amines or something like that.
OK. Sound good?
OK. So, hopefully I've allayed some of your fears.
Don't panic yet but get ready to panic in the next week or so.
And also get ready to take your game up a notch.
OK. So, that, you know, even if you have a bad time in 51C,
you can do pretty well on this class
if you're ready to work pretty hard.
You know, do lots of problems,
come up with creative ideas, et cetera.
OK. Discussion sections, these are mandatory.
This is especially important
if you're weak in organic chemistry.
Discussion sections are going to be run
in a problem solving format and this is your chance to show
that you could do arrow pushing with the best of them.
So, a lot of the problems in this class involve mechanisms.
And so, in discussion sections you'll have a chance
to demonstrate your ability to do mechanisms.
You'll get up to speed on doing these correctly, et cetera.
OK. So, again the first worksheet will be
posted shortly.
The first discussion section will start this Wednesday,
Mariam will be teaching that one.
And then after that it will continue.
OK. Now if you're on a Monday--
if you were scheduled for a Monday discussion section,
don't panic, what-- the material that will be covered
on Wednesday well then be covered on the next Monday.
OK. So, we'll have them slightly staggered throughout the class.
OK. And it turns that actually works out fine
because the midterms are on a Thursday and a Tuesday.
OK. So, there will be two midterms in this class
and there are no make up exams available.
They will consist of the full hour and 20 minutes.
There's going to be an emphasis
on arrow pushing and concept problems.
There'll be things like short answer.
There will be no multiple choice, there's going to be
like short essay type problems.
There'll be problems where you have
to design experiments, things like that.
OK. But lots and lots of arrow pushing,
so get ready for arrow pushing.
In addition, the other way that I'm going
to assign your grade is I'll be looking at two written reports
that you're going to submit in the class.
The first of these is a journal article report due,
unfortunately, on Valentines Day.
Happy Valentines Day from you chemical biology friends.
And in this one, in this report you're basically going
to be doing the equivalent of a book report but using an article
from the primary literature to provide their report.
I've already posted to the website an example of this.
In addition, instead of a final exam,
this class will have a mandatory proposal that's due
on the last day of class, March 14th.
OK. So, that's a mandatory proposal,
you can not pass this class without turning in the proposal.
But there's no final exam.
The proposal will consist
of an original idea in chemical biology.
Now I know this is daunting.
I've taught this class before.
I know that this is really intimidating.
Don't panic.
I will have a series of exercises for you this quarter
that will get you up to the point where you're ready to come
up with creative novel ideas
in the cutting edge of chemical biology.
So, you will be ready for this, you'll be ready to contribute.
And the good news is in chemical biology there's so much
that we don't know that's there's lots of room
for smart people like yourself to come
up with really great new ideas.
And I see this every year,
every year I would take the very top proposals from this class
and I can present them to the National Institutes of Health
and they would get funded.
OK. The best ideas I can put up for faculty ideas anywhere.
OK. So, I've seen that before.
And the other thing is I'm looking for a small idea.
OK. I'm not looking for, you know, the next Manhattan Project
or something like that.
I'm just looking for-- just give me a base hit, you know,
something that will work, that will teach us something new
about chemical biology.
And you're good.
OK. Quizzes, I will have a series of quizzes in this class
that will number between one and five, OK,
more likely to be one to two.
There will definitely be a quiz sometime in that last week
and the reason is our second midterm is in February
and the class keeps going until March.
OK. So, there will be an easy quiz,
the quizzes in general are designed to be easy.
They're basically, you know, recapitulate something
that you just saw on the board.
OK. So, we'll run these either at the beginning of the class,
at the end of the class
and it'll be something along the lines
of you just saw this mechanism, show me again how it works,
OK, something like that.
It just basically tells me whether
or not you're paying attention and who's showing up for class.
And by the way I'm delighted to see all
of you happy people out this morning.
Welcome. But I know as the class wears
on that you guys get very busy.
And of course the lectures will be posted online.
There has to be some incentive here to get you rolled
out of bed at 9:30 in the morning.
OK. So, we will have some quizzes.
It won't be too many and they won't be hard.
OK. That I promise you.
In terms of percent of your grade, those quizzes only count
for 5 percent the same level of participation.
Participation counts on both lecture and discussion and for
that matter even office hours.
OK. So me and Mariam and Krithika getting to know you,
that's how we determine the quiz scores--
or the participation scores.
And by the way, I will post all of these slides online.
OK. So, they'll be all posted to the website
so you'll have copies of them.
They're not posted now but they'll be posted shortly.
OK. Each midterm will count for 22 percent of your total grade.
The journal article report will count for 16 percent.
And then the proposal which is in place
of the final exam counts for 30 percent of your grade.
OK. So, it's a pretty even distribution there're lots
of opportunities for you to get feedback, et cetera.
Any questions so far?
Yeah. And what is your name?
>> Anna.
>> Anna.
[ Inaudible Remark ]
It is. I haven't talked about that yet.
Thanks for anticipating.
I'll get to that in just a moment.
OK. Thanks for asking.
And Steve?
No? What is your name?
>> Carl.
>> Carl, OK.
Carl.
[ Inaudible Remark ]
Yeah. No problem.
Carl's question is what if I'm assigned
to some discussion section that doesn't fit my schedule, do--
can go to another one?
No problem.
And you can even go to one one week
and a different one the next week.
No problem.
OK. And it is posted online or it's posted
on the syllabus exactly when the discussion sections will
take place.
Let met show you that.
OK. So, this is the course website.
OK. Notice over here that there are instructions
for the book report.
I'll change this very slightly.
For 2013, the instructions for the proposal,
I'll change this very slightly.
There are three examples of proposals that got an A
and then the syllabus.
OK. In the syllabus I've listed the discussion sections
where they meet, et cetera.
Feel free to go to any of these.
OK. Let me zoom through this.
This is online.
I'd like you to read this carefully.
I'm going to hold you to all of the provisions that are in here.
OK. So, anything that's written in here,
it's the equivalent to me saying it.
All right.
I'm not sure exactly why it is that's been cut off
in the right.
A lot of this recapitulates what I've just said.
OK. Let's get to this, Anna's question.
Over here, there will be-- let's see.
One moment.
OK. On February 21st, 2013, you will turn
in an abstract for your proposal.
OK. So, an abstract is a short condensate
of what your proposal is going to consist of.
This tells me whether or not you're on track.
And I'm going to use this as a way
to give you early feedback about your idea.
And tell you whether or not I think your idea fits the
definition of chemical biology.
Whether or not I think your idea is a creative one
or not so creative.
OK. So, this gives me a chance
to give you feedback before you turn in your proposal.
OK. And this abstract is worth 10 percent of the points
for the proposal assignment.
OK. So, in other words 3 percent
of your course grade will be determined by that abstract.
OK. Note that all assignments are due
by 11 a.m. on the due day.
There is a late policy.
But I hope that doesn't apply to you.
Questions so far?
All right.
Yeah? No. Just stretching all right.
There's some information here about adds and drops.
There's a frequently asked questions section.
Do I need to attend discussion sections?
Yes. Discussing paper, turning the final assignment.
Oh, if you have not taken all three quarters of Chem 51
or two semesters of sophomore organic chemistry.
You should drop the class.
OK. You're going to blown out of the water.
OK. So, you must drop the class now.
It's a prerequisite and then every year someone
slips through.
Don't take this class
if you haven't taken the full sophomore organic
chemistry series.
OK. OK. There's a whole thing on incompletes over here.
Academic honesty.
Unfortunately, we're going to talk
about this later in the class.
I do not want it to apply to you.
Major portion of your grade is going to be writing assignments
and so academic integrity issues loom large unfortunately
in this class.
Every year, I have to give someone F grade
on the assignment which ends ups turning into like a C minus,
D plus kind of deal because they try to plagiarize assignment.
Don't let that be you.
Let's make this the year where I don't have this problem.
Along those lines, if this is the year
where I don't have any plagiarism problems,
I will give an additional 3 percent higher grades.
So, I'll assign the grades and then I'll go through
and I'll bump up 3 percent of the course grades
to the next higher grade.
OK. So, if everyone in the class avoids having any plagiarism
or academic honesty issues.
So no cheating on the exams, no plagiarism,
no academic honesty I will bump up the grades by 3 percent.
OK. That means four, five of you at each level are going
to get a higher grade.
OK. So that means like four people, three or four people
who are going to get a B plus I'll move them up to A minus.
I'll take top-- the three or four top A minuses
and move them up to an A. OK.
That's the deal.
OK. We'll talk some more about this
because it's a slippery slope and it's best that we don't have
to have this conversation later.
OK. So, anyway, that's the information on the syllabus.
I'm holding you entirely to the contents of that syllabus.
So I'm expecting you to go home and read the syllabus carefully.
I don't have time to talk about every aspect of it now.
I'd like you to go home though and read it carefully please.
OK. Questions?
Questions?
OK. Skip that, skip that.
OK. Let's get started.
So, we already heard the question,
what is chemical biology?
How does it differ from biochemistry?
I gave you kind of a quick answer.
I want to delve into this topic a little bit further.
OK. So, here's the working definition of chemical biology
that we'll be using in this quarter and it's important
that you understands this.
This is the definition is using chemistry to advance an under--
molecular understanding of biology
at the level of atoms and bonds.
So, the way I know that we're talking at the level
of molecular-- at the molecular level is if we're talking
about atoms and bonds.
OK. And that's what I'm looking for in terms
of a definition of chemical biology.
There is a second corollary to this definition
which is using techniques from biology to advance chemistry.
And some examples of these are, for example,
using molecular biology techniques
to develop combinatorial libraries of chemicals
which is something that is one of the projects
that my own laboratory does.
OK. So, there are two parts of this.
Using techniques from chemistry to study biology
or using techniques from biology to solve problems in chemistry.
In both cases, these involve looking at molecules
at the level of atoms and bonds.
And that's where it's distinct from biochemistry.
Biochemistry also uses techniques in chemistry
but oftentimes, they're content with looking at molecules
as sort of amorphous blobs that are represented as, you know,
spheres or something like that in textbooks.
In this class, we'll be down at the level of atoms and bonds
and that's how you know we'll be talking about chemical biology.
So, later in the class when I ask you to come up with an idea
in chemical biology a proposal idea,
then you should be thinking at the level of atoms and bonds.
And then that tells you whether
or not your idea will be acceptable.
OK. So, chemical biology advances both chemistry
and biology.
And I wanted to give you a couple
of historical examples to this.
For my money, the very first chemical biologist was Joseph
Priestley, this guy over here.
He was a remarkable character.
So, he isolated oxygen and other gases.
OK. So, he was isolating these using electrolysis
and other techniques.
And he would isolate these in bell jars
and then he'd use these chemicals to study biology.
So, one of the experiments he did
for example was subjecting poor mice, mice that he would trap
from fields to these different chemicals that he was isolating.
And he found that the mouse for example can live in oxygen,
but could not live in many of the other gasses
that he was isolating.
OK. So that's a really interesting example
because he's using the very latest techniques from chemistry
to understand better how respiration works.
How organisms take in oxygen and at the same time,
it's using a technique from biology as a way
of solving a problem in chemistry.
And the technique in biology is, does the mouse live or die?
Does the organism-- can the organism survive
under these conditions to tell me something
about those chemicals, right.
Joseph Priestley didn't have any spectroscopy available to him.
So, he is using a technique from biology,
a very qualitative technique to be sure
by the method nonetheless to tell him something
about what's happening at the chemical level.
OK. Now Sir Joseph-- or Joseph Priestley had some radical ideas
about colonist in America and theological descents
that were going on in England at that time.
And I like to say that the very first chemical biologist had his
house burned by an angry mob who came rampaging
through his village with pitchforks and were
out literally to get his head.
And we had a proud tradition ever
since of iconoclastic thinkers and independent people
who were guaranteed to rile up the masses.
But of course, he's not getting burned at--
or his house is not getting burned
because of his chemical virtues.
This was then carried on by Sir Humphrey Davy who's shown here
at Royal Society of Chemistry conducting the experiments
on his colleagues.
He's having them inhale bags made
out of silk that include gasses.
And then he's looking at the violent excretions
that happened afterwards.
And so, this is just a classic woodcut from the period.
OK. Now, the other-- so, these are sort of early workers.
Perhaps historically, the most important experiment
in chemical biology was done
by the great Friedrich Wohler in 1828.
Here's a picture of him.
Notice that these guys are pretty young.
OK. These guys, you know,
they were doing these stuff in their 20s.
OK. They're not much older than you.
Any of you in this classroom five years from now,
you could also be doing stuff
that would change how we think about the universe.
OK. That's the way science works.
That's one of the great things about science.
OK. So, don't think about this
as being done only by old people.
It's not. It's done-- These great ideas are often times done
by young iconoclast who have clever ideas
and just want to push the balance.
OK. So here's Friedrich Wohler, 1828,
he is running an experiment in his laboratory
where he's running this silver cyanate experiment
where he's trying to do what would
like just the most pedestrian of exchanges of salts.
OK. So, what he's trying
to do is synthesize ammonium cyanate using silver chloride
which he knows will precipitate out.
Recall from Chem 1 that precipitates
out in a white powder and he's doing this
by simply mixing silver cyanate together with ammonium chloride.
And he's expecting when he heats this
up that the silver chloride will precipitate out
and he'll be left with ammonium cyanate.
It turns out that's not what he got.
OK. That was not the product that occurred.
Instead, what happened was he got out this other product
that crystallized out of the reaction flask.
And when he smelled this other product,
he knew immediately what it was, what he smelled was urea.
And urea had been isolated from urine, from dogs and humans.
And so it was known that urea is a known compound.
And back then, the primary way
of characterizing the chemicals was by their smell,
by their taste, you know, some gross physical properties.
And because urea has a distinctive smell,
he can readily characterize this.
Now, here's the significance of this discovery.
What Friedrich Wohler recognized was that this urea was identical
to the urea that's attained from dogs and from humans.
But the difference is this did not come from a living organism.
In other words, using just mineral sources,
you can make the same chemicals
that are found in living organisms.
So, there's not some sort of special property
that animates the chemistry of living organisms
that some how makes it special.
Instead, it's going to be governed by the same rules
that are found in chemistry that's outside living organisms.
OK. And this is really important because at that time,
there was this notion
that living organisms would have some sort of special spark
that in someway would make them alive and make them--
make their chemistry unique and special.
And what Wohler is showing us by this experiment,
is that in fact there was nothing unique and special
about the chemistry inside living organisms.
OK. So, these are great examples of using chemistry
to understand biology at the level of atoms
and bonds in the case of urea.
Let's move on.
Another principle that underlies chemical biology is evolution.
We're going to be talking a lot about evolution in this class.
And so the reason we're going to be doing this is first,
it simplifies knowledge.
And second, it's going to guide experimental design.
And here're two views of the great Charles Darwin.
We can't talk about evolution without making reference
to Charles Darwin who articulated in, you know,
150 years ago, much-- you know, the principles behind evolution.
There are two steps to evolution.
The first step is to diversify, to generate a diverse population
of molecules, of organisms, of phenotypes really.
And then the second step is to select for the fittest
from this diverse population.
I'll explain the word phenotype in a moment don't panic
if you didn't understand that word.
So, there're simply two steps here.
Select for-- generate diversity, select for fittest.
These steps are then repeated again and again
to evolve organisms that can solve some sort of problem.
In terms of chemical biology,
we think about generating diverse populations as ways
of shuffling together-- shuffling around biooligomers
in combinatorial manner, in combinatorial manners.
And I'll show you that in a moment.
And we often do experiments
that involve some selection for fitness.
We're going to make a large population of molecules,
mix them up and pick out the ones that are most--
that can best fit a criteria or set of conditions.
This is a very powerful principle that allows us
to make progress very quickly in chemical biology.
And this is used as a technique by hundreds
of laboratories in the field.
OK. So, we use evolution not just system sort
of theoretical underpinning.
But we also use this as an experimental framework.
And I encourage you when you're thinking about proposal ideas,
think about evolution as a tool to help you speed
up getting towards molecules that do stuff for you.
OK. So this is used extensively.
Another way that's used extensively is it's used
to organize knowledge.
When we talk about say the ribosome, which is the machine
that translates mRNA into proteins.
And I'll show you what that looks like in the moment.
I don't have to talk to you about some sort
of special ribosome that's found exclusively in humans or dogs
or something like that.
Because it turns out that the same mechanism used by ribosomes
in humans is also used by bacteria.
It's even the same mechanism used by Archaebacteria,
a different stem on the tree of life entirely.
And so, what this means then is that, I don't have to teach you
about the special chemistry of humans.
I can talk about the chemistry that underlies on all organisms
on the planet because we all evolved from common ancestors
that solved these mechanistic problems in chemical biology.
OK. So, this provides the powerful approach
to evolve molecules which I alluded
to in the previous slide, but equally importantly,
this helps us to organize knowledge
and make it much simpler for us to talk
about universal chemical mechanisms
that underlie all life on the planet.
OK. So, speaking of sort of universal principles
that underlie all life in the planet, the Central Dogma
of Modern Biology is use--
is going to appear in multiple ways throughout this quarter.
In the first way, this is how we've organized the textbook
that we'll be using this quarter.
OK. So, the textbook has different chapters.
And it's organized according to the Central Dogma.
So, the Central Dogma describes all biosynthesis
that takes place in cells and on the planet.
OK. So, everything that you're going to synthesize
in your cells is in some way encoded by this Central Dogma.
The Central Dogma tells us that the DNA found in nuclei
in eukaryotic cells is the blueprint upon
which all biosynthesis is based.
This DNA is transcribed into RNA
and then translated into proteins.
OK. So, this is the earliest diagram
by the Great Francis Crick
who recognized the far reaching implications on this Dogma.
Very early on, OK, this is his earliest example
of where it was articulated.
It looked just like this.
We know now, for example, that there is in fact--
this dash line over here is in fact a real line.
There is an enzyme reverse transcriptase
that can convert RNA into DNA.
But this line over here where RNA is used a template
to make new copies of it self, this line never materialize.
We have not found it in many years of looking.
In fact it would be a great chemical biology proposal
to come up of the way of doing that.
OK. So here's a different way of looking
at the Central Dogma of Modern Biology.
So, at the very top, DNA, this biopolymer up here is going
to encode messenger RNA and in fact all RNAs.
This-- The conversion of DNA
into the complimentary RNA takes place using an enzyme called
RNA polymerase.
OK. This is nice because it's going
to be polymerizing RNA, this make sense.
I'm going to be referring to enzymes today
and in future classes, enzymes are proteins
that catalyze chemical transformations.
OK. So, these lower the transition state energy
for key reactions that take place in the cell.
And here's our first example of this.
The enzyme RNA polymerase that's responsible for transcription.
In addition, there's an enzyme DNA polymerase
that allows replication of the DNA to make new copies
of the DNA when the cell has to divide.
OK. Here's the ribosome that I alluded to earlier
on a previous slide that is responsible
for translation of RNA into proteins.
This Central Dogma continues
as proteins then can catalyze reactions that lead
to other biooligomers that are going
to be very important in this class.
For example, we're going to see a class
of biooligomers called terpenes that are used in--
used by plants and microorganisms for signaling.
Polyketides, a class of molecules that's very important
as natural products for antibiotics
and other pharmaceutical uses.
And then oligosaccharides,
the glycans that decorate the surfaces of your cells
and play key roles in protein folding and key roles
in cell base signaling.
OK. So, here's my plan for this quarter.
We're going to have two lectures about each
of the biooligomers that's depicted here.
OK. So, next week, I'll talk two lectures about arrow pushing.
Week three, we'll have two lectures about DNA.
Week four, two lectures about RNA.
Week five, two lectures about proteins.
Week six, oligosaccharides.
Week seven, polyketides.
Eight is terpenes.
Oh, actually, I'm sorry.
I'll have four lectures total about proteins.
I can't resist.
I'm a protein guy.
So, yeah, so we'll have a total of four lectures about proteins,
but everything else we'll have two lectures about.
And we'll be covering a chapter a week in the class.
OK. So, necessarily some of the material
of the textbook will be left aside.
OK. Everyone still with me so far?
>> Yes.
>> OK. So I told you that everything that synthesized
in the cell is synthesized in a deterministic way,
starting with the DNA up here.
And it turns out that's not strictly, strictly true.
And I want to explore a little bit more
about what the subtleties of this concept.
So, first of all, we need
to define what is the unit of synthesis?
So, proteins and DNA, oh sorry,
DNA is read out in units called genes, OK,
where each gene is going to coat a single protein.
Genes have two essential parts, an on-off switch
and an express sequence.
The on-off switch is where transcription factors bind.
These are proteins that can encourage RNA polymerase to bind
to the start of this gene and encourage it
to start transcription.
OK. Similarly there's other-- if there's promoters,
there's also other ways
of shutting off the synthesis as well.
It gets complicated.
This transcribe region then becomes the messenger RNA
which is then translated by the ribosome
into the protein down here.
OK. So, here is an example
for a transcription factor binding to DNA.
Notice that the DNA has a structure
that can nicely accommodate the structure of this protein.
I'm going to be talking a lot more about proteins later.
But I want to tell you about a convention
that we're going to be using.
OK. So, proteins hopefully as you know are composed
of amino acids that are strung together by amide bonds.
OK. If what I told you totally doesn't make sense, read--
go back and read the reference supplemental organic
chemistry text.
OK. So, when we look at these amino acids and we just look
at the amide bonds and the carbon that's alpha
to that amide bond.
We can trace out that back bone using these ribbon structures.
So, these ribbon structures do not look at the side chain
of amino acid, rather they simply trace out the sort
of the scaffolding back bone of the protein.
OK. So, that's what these ribbon diagrams will look like.
And then here's a structure of DNA down here.
Notice that this alpha helical ribbon, this curly,
cute ribbon fits neatly into the DNA's major grove.
We'll talk much more about that later.
OK. Let's take a look at the world's smallest gene.
This is the Guinness Book of World Records for smallest gene.
In this case, this gene encodes for microcin C7 or the gene--
the protein it will encode for is called microcin.
Microcin is a translation inhibitor.
It's a protein.
It's-- Well, it's a peptide,
short piece of protein called a peptide that's used
by microorganisms to kill off their neighbors.
OK. So, the microorganisms that grow in your skin,
that grow in the, you know, far recesses of this--
of the walls, you know, that grow all
around you are constantly fighting chemical warfare
with each other.
OK. Their goals are to kill off their neighbors
and then give themselves more resources that allow them
to grow better, OK, to grow faster and to be more populous.
OK. And microcin is a good example of one
of those antibiotics or compounds
that kill other organisms.
OK. And this is actually a very complicated binary toxin.
On the one hand, there's this peptide over here
that allows the microcin to be transported
into the competing bacteria.
OK. So, the bacteria, look at this complicated thing,
they sniff at the peptide region and think, "Oh,
that peptide looks yummy.
And if I eat that, I'll get amino acids as a source
of building blocks for my own proteins."
OK. That's kind of like the bait.
OK. So, the competitor picks up the bait,
transports microcin into-- the microcin c7 into it--
into itself and in which case,
enzymes in the competitor then break a part this peptide.
And then unveil the translation inhibitor down here that shuts
down translation by the ribosome.
This is very bad news for the competitor, right?
If the competitor organism--
microorganism can not translate mRNA into proteins,
it cannot live, it cannot divide,
it will die very quickly.
OK.
And so, in the end, what we're seeing is
that the smallest gene is rather complex.
Its toxic fragment is highlighted over here
and the rest of it also plays a key role as well.
OK. So, this-- to make something as complicated
as this requires a large number of genes that are lined
up over here where each one
of these arrows represents a sequence of DNA.
OK. And we'll talk more about the directionality
of the arrows, you know, later, week three.
For now don't get too worked up about it.
Notice though that it takes several genes
to compose this toxin.
OK. So, some of these genes are doing things like adding
on this non-peptide like toxic fragment.
OK. So, some of these genes
up here are encoding various enzymes.
OK. So that's this microcin, this mccB, mccD, mccE enzymes.
So these enzymes are adding on stuff and modifying the peptide
that was otherwise encoded by mccC in the center over here.
OK. I'm sorry, mccA that was encoded up here.
Now, at the end of this,
even though this is the world's smallest--
you know, smallest gene delivering a tiny
little peptide.
The resulting peptide is still fiendishly complex.
OK. This thing includes a large number
of different stereocenters indicated
by the dashes and the wedges.
And furthermore, this isn't the half of it, right.
This is just very simple example.
The proteins we'll be talking about,
the proteins I've been showing you today, for example,
the transcription factor, consist of hundreds of subunits,
hundreds of amino acids, each one likely
with its own stereocenter.
And so the chemical biology considerations become enormous
when we start looking at this in greater detail.
OK. All right.
So, we've looked at a gene let's talk next
about the collection of genes.
All of the genes together that are found
in an organism are referred to as a genome.
Here's one representation of the genome
of the bacteria model system, bacteria called E. coli.
We'll be talking a lot about E. coli.
I'll have another slide about it in a moment.
This is used extensively
in chemical biology laboratories including mine.
And its genome looks like this.
Where in this representation it's shown as a circle
and each one on these colored bars tells us something
about the size of the gene, whether not it's GC--
whether it's GC richness is, et cetera.
OK. So, reading out the information here,
not so important.
Suffice it to say that the human genome has
around 24,000 or so genes.
And when you compare that against almost any other machine
that we have around us,
this number sounds ridiculously small.
One of the challenges, however,
is even though we have this complete parts list
for a simple organisms like E. coli,
it's not clear what each one of these parts is doing.
And so a goal of functional genomics and a goal
for that matter of chemical biology is to try
to make better sense of this parts list.
OK. And let me show you what I mean on the next slide.
OK. Let's imagine that you had a transmission from a car.
OK. And imagine that you had parts list
of all the different gears found in that transmission.
OK. I could tell from some experience that just starring
at those different gears, even, you know, starring as hard
as you possibly can and using your best, you know,
sort of logical reasoning, you're going to have really,
really hard time trying to put together each one
of those little gears.
OK. I don't care how smart you are.
It's a really hard problem.
And so, we have that same problem when we look at genomes.
When we look at genomes, it's not clear what each one
of these parts are doing.
And one of the roles of chemical biology is
to help us annotate genomes and teach us about what each one
of those parts is doing in terms of the larger machine.
We'll talk some more about that.
There'll be a topic called Functional Genomics.
OK. So chemical biology helps us fill in the dynamics
of the process and how these pieces fit together.
OK. So, one way that it fills in dynamics,
dynamics means change overtime is an important area
of chemical biology develops new tools that allow us
to see molecules at the single molecule level
and understand how they change overtime.
How they dynamically interconvert it
to different speeds and things like that.
And Mariam is one of the world's experts at this.
She can tell you more about this.
Now, another big challenge that we have is
that often times we have big differences in genomes
that lead to the same species.
Here for example are three different strains
of the model bacteria, E. coli.
OK. So, here're three different strains and only 40 percent
of proteins are shared between these three.
Notice that they look identical, they're all the same species
because they can mate, they can exchange DNA with each other
which in terms of bacteria turns out is not necessary the same
as being same species.
But in any case, these are named-- all named E. coli,
yet they have vast differences in what DNA they've picked
up from their environment and from other microorganisms.
So, simply knowing the parts list is not going to be enough
for us to explain what's similar and different
between these organisms.
OK. And for that matter when we start looking at different--
when we start looking at different organisms
from the same population, we see a similar sort
of diversity despite having very,
very, very similar genomes.
OK. So, I've been talking to you both
about humans and also bacteria.
I need to hopefully just very briefly review for you
that the differences in those organisms are vast.
OK. I'm hopefully not telling you anything you don't
already know.
Bacteria are classified as prokaryotes,
humans and other multi-celled organisms or organisms even
that are single cell that have multiple compartments
in them are classified as eukaryotes.
I'd like you to or I'll tell you that in a moment.
The big difference here is
that the prokaryotes don't have any compartments
for the most part.
The DNA has kind of organized into nucleoid,
but for the most part there are no compartments in the inside
of the cell of a prokaryote.
Whereas when we look at eukaryotes under the microscope,
we find something totally different.
What we find is a bunch of organelles
which are these little compartments in here.
OK. And these organelles have different functions
for the cell rather than being just the big bag that has all
of the functions being carried out kind
of randomly within that bag.
OK. Now, getting back to this idea of genomes,
nearly identical genomes can lead to very different people.
So, even though our genomes are 99.9 percent identical we see
vast differences.
So, this is a challenging concept
but what's happening here are vast differences
in transcription underlie these different phenotypes
that are observed
where phenotype is the physical outcome of the gene.
OK. So all of us have roughly the same genomes,
yet the phenotypes that come out differ at the cellular level
by different transcription levels that program our cells
into having different functions.
So, even though each one of these cells has the same genome
that cells end up having different functions
by having different transcription levels
of different sections of the gene--
different genes within the genome.
And furthermore at the organismal level this plays
out in other ways as well, OK,
also at the level of transcription.
OK. So, here're six different human cells
and you can see vast differences in their morphologies,
their shapes, et cetera.
And for that matter, I don't think I have to work hard
to convince you that these have very different functions inside
the organism, in this case humans.
OK. So, I showed you briefly a prokaryotic cell over here,
I'd like you to memorize all of the structures.
Everything that's labeled here and labeled in the book--
the textbook, OK, you should memorize the structures.
And along those same lines I'd like you
to memorize all the parts that are labeled
in the textbook for eukaryotic cell.
OK. So you should know basically the simple anatomy of a cell.
OK.
>> Do you know its functions as well?
>> The basic functions.
If it's in the book, yeah, I like you to know.
OK. So, we've looked at DNA.
DNA gives us genes, which gives us genomes.
Next section down on the Central Dogma is RNA.
So, from RNA the complete collection of RNA transcripts
in a cell tissue organism is called the transcriptome.
OK. So here's the DNA, the genome of the organism.
Here's a bunch of RNA transcripts and the number
of copies that each one of these transcripts is controlled
by transcription factors that I showed you earlier.
OK.
That was the alpha helix fitting into the DNA.
If that transcription factor is very effective at grabbing
on to RNA polymerase then you'll get more copies
of the mRNA transcript being produced.
OK. So these more copies
of the transcript being produced can give rise
to very different phenotypes of the organism.
So ultimately a lot of the phenotypes
that observed are being driven by differences in transcription,
in addition to differences in the encoding DNA.
Everyone still with me?
OK. Things are going to get a little bizarre next.
It turns out that the RNA that's encoded
by DNA is further diversified by a process called RNA splicing.
OK. So RNA splicing takes the RNA that's encoded by the DNA
and then sort of shuffles it around very subtly.
OK. And the results are a bunch
of different mRNAs encoding potentially different proteins
down here.
OK. And the results sometimes are dramatically differences
in the result in proteins.
So these proteins, the consequences
in this can be proteins that have very different function
from the starting mRNAs.
You can end up with two different proteins splice
variance of each other that are encoded by the same DNA
that have different results inside the cell
in different phenotypes.
OK. Now there's going to be further diversity
but just to organize things.
So we've seen at the DNA level, the collection
of all genes is called the genome.
We've seen at the RNA level, the collection
of all RNA transcripts is called the transcriptome and then
at the level of proteins, the collection
of all proteins is called the proteome.
OK. This is-- There is a sort
of a neat organization to all of this.
OK. Now what I'm showing you,
I've already showed you this representation
of the genome for E. coli.
This is a way of representing the transcriptome using a
technique called RNA microarrays.
We'll talk about this more in week four.
And then you can do a similar thing that make a big collection
of all the different proteins found in the cell of organism
or tissue and array these on microscopic slides as well.
OK. So, all these techniques are ones that we'll talk
about later in the class.
OK. So we've talked about how you can start
with an RNA transcript.
Oh, question over here.
>> I just wonder what the RNA splicing--
>> Yes.
>> -- for the message RNA.
[ Inaudible Remark ]
>> OK. So what is your name?
>> Ashley.
>> Ashley.
OK. So Ashley's question is what actually gets translated
on the messenger RNA?
>> Yes.
>> And--
[ Inaudible Remark ]
And there's what?
>> In translating the mRNA.
>> Yes, what actually gets translated into proteins
from the messenger RNA?
OK. That's your question right?
>> No.
>> No.
[ Inaudible Remark ]
Yes.
[ Inaudible Remark ]
The axons?
[ Inaudible Remark ]
Oh, OK. So your question is more subtle than that.
OK. So could I defer that until we get
to week four which is the RNA?
>> OK, yeah.
>> OK. Good question.
We'll get an answer.
Other questions?
OK. So we've seen how splicing can start with transcripts
and then add additional diversity.
It turns out that proteins are also subject
to diversification as well.
So after the proteins are synthesized
by the ribosome during translation, these are subject
to further diversity in a couple of different ways.
OK. The first way is for the proteins
to be modified chemically on their surface,
and so one example of this is an elongation factor II.
So this is posttranslationally modified
to produce this functionality up here called diphthamide.
OK. So the protein is enzymatically converted
from having this imidazole functionality up here
into having a diphthamide functionality.
This is absolutely required for translation by this organism,
organism being humans.
OK. So elongation factor II that's been posttranslationally
modified is required for translation to take place.
However, the diphtheria toxin has a way
of cleaving off this diphthamide.
OK. When that happens,
that prevents protein translation from taking place.
OK. Diphtheria toxin fascinating,
it's an effective way of killing cells.
What's important here though is this notion that even
after the proteins are synthesized,
they're further diversified by chemical reactions
that take place on their surface.
Because this takes place after translation, these are referred
to as posttranslational modifications.
OK. Post meaning after; translation, modifications.
Translational modifications.
And this is really important.
This means that we can start, let's say, 24,000 or so genes
in the genome get, you know, say 50,000
or 60,000 different splice variance,
get say 60,000 different proteins
and then further diversify those 60,000 different proteins
into to 200 or even more thousand different proteins.
So in the end although our genomes look relatively
uncomplexed at the level of 24,000 or so different parts,
the true number-- this vastly understates the true number
of parts which is much, much larger due
to reactions like this one.
OK. Furthermore, these proteins go off
and catalyze other functions
within the cell leading to further diversity.
OK. Everyone still with me
in the posttranslational modification?
Let me show you what I mean.
I refer to this as posttranslational processes.
So, this is the process by which proteins catalyze as enzymes,
the production of other molecules, oligosaccharides,
glycans, polyketides and terpenes.
OK. So, once the enzyme is made, it's just the start.
After that, all kinds of other things take place.
OK. And this is-- proteins can be covalently altered
by enzymes.
OK. That's the modified proteins that I showed you
on the previous slide.
In addition, there are spontaneous processes
that alter the surfaces of proteins.
OK. So, for example, oxidation of proteins is sort
of an unavoidable consequence
of having a metabolism that's dependent upon oxidation, right,
and producing oxidation products.
So, there are some strong oxidants
that are produced by your cells.
And those oxidants will come along and modify the surfaces
of proteins, spontaneously, OK,
using thermodynamically accessible reactions.
And so these are examples of posttranslational modifications.
In addition, proteins themselves will catalyze reactions
that will synthesize these molecules down here
which again are part
of the Central Dogma, their biooligomers.
Now, one thing I have to tell you is that while I told you
that the Central Dogma
in a deterministic way determines everything that's
been synthesize by the cell--
while it determines everything synthesize by the cell,
it's not purely deterministic.
OK. And there's an element of randomness to all of this.
OK. And that's what I want to show in the next slide.
OK. This is-- we're going to have randomness in the sense
that the Central Dogma will dictate the identity of enzymes
and then these enzymes are going to go up and catalyze reactions
that will not be determined by the DNA.
That will be at some level a little bit randomized.
OK. So, one good example of this is the process
of appending oligosaccharides to the surfaces of proteins.
OK. So, R over here is meant to represent a protein and each one
of these shapes is meant
to represent a different carbohydrate, glycan,
that's being-- that's going to be attached
to the surface of the protein.
OK. Now, the way this works is that each one
of the enzymes that's going to do this attachment is encoded
by some gene up here, encoded by the DNA, translated--
transcribed into messenger RNA which in turn makes the protein,
the enzyme that's going to catalyze bond formation
to add this glycan onto the oligosaccharide.
OK. What's less clear though is, you know, small variations
in the resulting glycans down here.
So, for example, enzyme 2 makes this bond,
if there's enough enzyme 2
around maybe it makes another bond.
Enzyme 11 makes this bond,
but maybe if there's enough enzyme 11
around maybe it makes another bond over here.
So, there's diversity in the resulting structures
that are biosynthesized by the enzymes.
OK. Furthermore, even though I'm lining up the enzymes
in this order, the order of the genes in the genome is unrelated
to the final product that results in this glycan
on the surface of the protein which eventually appears
in the surface of the cell.
So, there is considerable heterogeneity
in these posttranslational processes.
Both in terms of modifications in the sense that some
of these modifications are occurring spontaneously just
through thermodynamically accessible reactions.
And furthermore, when these posttranslational processes are
catalyzed by enzymes, there is considerable stochasm,
randomness in terms of what the resulting structures will be.
OK. So this is one of these kind of mind-blowing concepts
that we have to get comfortable with.
OK. That we can't
in a deterministic way know every single molecule
in a cell to a precise level.
OK. Everyone comfortable with that concept?
OK. Don't look so moppy-eyed and downcast.
At the end of this class, hopefully,
you'll at least have a framework to understand it, OK.
OK. So, I want to switch gears now and talk
about some other principles, different types of techniques
that you need to know that are going to make our lives
so much easier in understanding the experiments behind
chemical biology.
OK. So earlier, I told you that an important principle
in chemical biology
or an important technique used extensively
in chemical biology is to make large diversity,
a large diversity of molecules, and then sift
through this diversity to find a few molecules
that do something special.
OK. This is a technique of molecular evolution.
It's used extensively in chemical biology.
So, there's going to be one equation in today's lecture
that I need you to know.
And this is the equation that determines the diversity
of a collection of molecules.
That diversity, the number of oligomers
that results is the number of subunits raised to the power
of the length of the oligomer.
OK. And let me try to show you this in action.
OK. So, let me turn on some lights here.
OK. So let's start with DNA.
Let's make a big collection of DNA.
So, DNA consist of four bases, OK, A, C, G, and T. Again,
we'll talk some more about their chemical structure in a moment.
Let's try to imagine then that we're going to make a collection
of all possible tetramers.
OK. OK. Number of possible DNA.
Let's make it pentamers.
OK. OK. So the number of possible pentamers is going
to be equal to the number of subunits raised
to the length of the biooligomer.
OK. So, this-- the number of sub units is four,
that's the number of bases.
The-- Raised to the power of 5 that's
because we're making pentamers.
OK. If we wanted to make-- OK, so this is example of five-mers.
If we want to do ten-mers, again,
we'd have 4 raise to the 10th power.
OK. OK. So this is a very simple equation, very, very useful.
It can tell you very rapidly whether
or not the experiment you've proposed is reasonable, right.
If you propose something, that's going to fill this room
with DNA probably not so reasonable, right.
That's not practical.
But if you propose something that you could fit and say,
a 1 ml test tube, totally reasonable, or 1 ml tube,
[inaudible] tube, that would work.
OK. OK. Any questions about this formula?
You ready to apply it?
OK. Good. OK.
One of the great feelings of teaching a class
like this one is that the example problems that I'll do
for you where we applied equation or whatever,
inevitably are a lot easier than the ones
that appear on the exam.
And I apologize about that.
That's kind of-- that's part of pedagogy I guess.
OK. Now, it turns out that chemical biologists apply this
to DNA, but they also apply it
to much more complicated molecules.
So for example, we can do a combinatorial synthesis
of a series of molecules that look like this.
OK. So, we could do, we can setup a modular architecture
to allow combinatorial synthesis that in a way similar
to composing biooligomers will result in molecules
that have modules that have been tethered together.
OK. So for example, this is--
this is a framework called the peptoid.
OK. And so instead of a peptide
where the peptide would have a side chain coming
out on the alpha carbon over here.
Instead this had side chains coming out on the nitrogens.
You can very readily make a large combinatorial library
of these peptoids and make a great diversity
of number structures using exactly the same formula
that I showed on the previous slide
to calculate the result in diversity.
OK. And let me show you how that work.
If you have 20 subunits,
so you have 20 different possible building blocks,
and you're going to make three-mers,
then you would have 20 to the power of 3,
20 raised to the third power would be the result
in diversity of that library.
OK. Where a library is a collection of diverse molecules.
OK. So, this idea
of combinatorial diversity applies both at the level
of shuffling around biooligomers and is applied in biology.
But equally importantly it's used as a principle
that underlies chemical synthesis in chemical biology
as well, including the chemical synthesis
that you learned about back in 51C.
OK. And we can get much more complicated and make libraries
of benzodiazepines which are shown here.
And this is an important class
of small molecules that's very commonly use
in many different drugs.
OK. Why don't we stop here?
When we come back next time, we'll be talking
about diversity of biology.
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