David Baker (U. Washington / HHMI) Part 1: Introduction to Protein Design

www.ibiology.org/ibioseminars/...
Lecture Overview:
Baker begins his talk by describing two reciprocal research problems. The first is how to predict the 3 dimensional structure of a protein from a specific amino acid sequence, while the second is how to determine the amino acid sequence that will generate a new protein designed to have a specific structure. Baker’s lab is addressing the second of these challenges by developing computer programs (such as Rosetta@Home) that calculate the lowest energy, or most likely, structures for differently folded amino acid sequences. Baker explains how his lab can design a new protein structure, not found in nature, and using the computer programs they have developed, determine the amino acid structure. It is then possible to back translate to the DNA sequence and synthesize the gene that can then by used to make the protein. When the structures of these synthesized proteins are determined by crystallography and compared to the predicted structures of the designed proteins, they are found to overlap very closely demonstrating that the protein design algorithms work well.
In the second of his talks, Baker tells us how his lab has moved beyond designing new protein structures to designing new protein functions. The first example he describes is the development of an inhibitor of the influenza virus. Baker’s lab designed a protein structure that fits into a highly conserved region of the hemagglutinin protein found on the surface of influenza. Preliminary lab data suggests that this designed protein protects mice from infection with the flu virus. Baker also describes experiments in which proteins were designed to fit together and build multicomponent materials such as nanocages, nanolayers and nanowires.
Speaker Bio:
David Baker received a BA in Biology from Harvard University and a PhD in Biochemistry from the University of California, Berkeley. Currently, Baker is the Head of the Institute for Protein Design and a Professor of Biochemistry at the University of Washington, and a Howard Hughes Medical Institute Investigator. His research utilizes both experimental and computational methods to study the design of protein structures, and the mechanisms of protein folding, protein-protein and protein-small molecule interactions.
Baker’s lab developed the crowd-sourced protein folding design programs Rosetta@home and Foldit. Learn more about these programs in Baker’s iBioMagazine talk and at his lab webpage www.bakerlab.org/static/ .
Baker has won numerous awards for his work including the Raymond and Beverly Sackler International Prize in Biophysics in 2008. Baker is a member of the National Academy of Sciences and the American Academy of Sciences.

[@brendansullivan4872]

This guy is an amazing individual and I hope he goes far in life.

[@saulbraydon5010]

instaBlaster.

[@twerktospec]

​@@saulbraydon5010sounds like my ex wife!

[@think_tank5603]

And here we're in the Alphafold/Rosettafold era. Kudos to these guys who worked hard to achieve the solutions.

[@natalyawoop4263]

David Baker was one of them. He's the best in the world at protein design and folding.

[@reyesdiegoarmando894]

I'm about to get my bachelors degree in Biochem. Eng. down here in Mexico. People like Mr. Baker inspire me. Great content

[@Chiranjit21]

So unique and motivated work. Thanks for sharing.

[@nicholaswong2992]

Very well paced and interesting

[@tessalittle6244]

I remember your work so well early 2005 when I was finishing off my PhD in protein folding. Here we are in the days of youtube and myself playing with water clathrate structures and nanobubbles

[@nitinchalla782]

loved it, thank you so much for uploading this.

[@davidkincade7161]

Great, will living things use these??? One wonders if there is an information differential between made in lab and made in cell??? Thanks

[@Elephantine999]

Interesting info and challenge. Nice graphics and good explanations. Thanks. Do you ever think (or worry) about making prions?

[@Bannanakick]

Hi, Im currently working on a presentation for my studies about that exact theme. My Information’s are based on an article from the Nature magazine from the 15th September of 2016. In the article the scientists also use the Rosetta program to design proteins. In my understanding they first try to build the carbon backbone structure by finding the lowest energy state, and then they try to add the different sidechains for the tightest packing together with the lowest energy possible. Here is my question: Don’t alpha helices and ß sheets need specific amino acid residues to even exist, at least at some places? If so does the program calculate these specific amino acids into the primary structure to stabilize the secondary structure? Ps: The name of the article is: The Protein World

[@vigneshs5286]

I too have the same question have u got the answer

[@bruv5184]

Answer?

[@petersq5532]

how do you solve the problem with conformation distortion between bound and empty active centre. you probably need a certain deviation from minimal energy hole to allow flexibility and reactivity to substrates do you have a figure how much the predictive success when the in vivo folding matches to the in silico one?

[@rebeccakane8854]

I am confused why would you need a deviation from minimal in order to allow for flexibility and reactivity to substrates?

[@petersq5532]

@@rebeccakane8854 it is because interaction and ligand bindings cause different level of comformation changes and new interactions. so the new conformation most likely on a different energy level.

[@susanmann5286]

He is one of my docs'. Believe me! He has/is!

[@someguy1576]

And I thought that the conformation that a protein adopts isn’t necessarily the global energy minimum, but rather a local energy minimum, where the protein would have to overcome a barrier to adopt the global energy minimum

[@juanzegarra5244]

I literally cried during the protein folding sequence, such beautiful and inspiring work

[@freedom21h]

Thank you for this great video.

[@kamilaltug5670]

As a machine learning engineer without knowing anything about biology and protein, Can I be expert on it if I work hard? Im super ubber excited over this topic but a bit scared.

[@bmbxw9201]

this man is a super super smart guy.

[@danieltaylor6708]

How to send the design to the new protein?

[@surose5229]

Just awesome! I would like to join your team

[@someguy1576]

I thought each amino acid could take 10 different conformations.

[@tedvga]

Truly Amazing, thank you!

[@anonviewerciv]

Protein structure is complex. (2:22) 10:30 Design principles.

[@oluwaboriatunwa1123]

Amazing!

[@rebeccakane8854]

WOW!!!!

[@charlesdale2600]

This video keeps me PhD movitated

[@hobog]

don't be demotivated

[@gizachewdiga]

Best illustrations on drug efficacy, agonist, antagonist, protein design, and computational description of protein design ( Lineard potential, Hydrogen bonding model, and Monte Carlo Methods) and experimental methods particularly Nuclear magnetic resonance (NMR) and magnetic imaging. Thanks.

[@twerktospec]

The more this all makes sense the scarier it gets

[@wormholetimes9839]

awesome, let's suppose sometime in the future we reach the level that we are capable of creating all essential elements in 3d all way down to electrons, program all laws of physics of the universe on a molecular level, start a virtual universe by launching the big bang in virtual reality and watch it as it evolves when all these elements randomly combine and interact with each other? will it evolve to produce intelligent 3D human beings capable of thinking and doing the same in their virtual reality? and.. are we the product of such achievement?

[@esrefcelikcelik8789]

It is a theory that random processes randomly created the life(!) accidentally. Personally I do not support it, but saying that The God created the life does not help much. So we should try our best to learn the universe and life. The more we learn, the more we believe in God.

[@luisp1375]

...aah...

[@iliketopwn6789]

AYE YO YALE BIO 101 TURN UP

[@sarahsotomayor3450]

catch me watching this 1 am the night before section lmaooo

[@laurelcook9078]

*Oh dear god*

[@Raphi]

18:50 "you see that the crystal structure is nearly identical to the design model" doesn't look like it to me

[@KenJackson_US]

Fascinating. Designing, optimizing, implementing and integrating custom proteins. I had no idea this was possible. It's worth noting, however, that the discovery of the magnitude of intelligently-directed computer resources needed to make one protein is a strike against the possibility that undirected natural processes could have come up with any protein.

[@theultimatereductionist7592]

Wrong. False.

[@KenJackson_US]

What's wrong, Ultimate? Wrong that there's too much complexity for proteins to have come about by chance? There are over 10^130 ways (permutations) to construct a small protein with 100 amino acids. But only a very small number of those will work for a particular function. How could any natural process select correctly against those odds?

[@woodbmx213]

@Ken Jackson I can suggest you one interesting book "The Selfish Gene" by Richard Dawkins. It talks quite a lot about evolution and other related stuff. I think what is false that you think that nature has to come up straight away with a protein out of nowhere, it actually does not work that way. Everything is build up step by step, if the step gives at least a minor advantage to the organism compared to the previous organisms, the organism will have a higher survival rate and more most likely more offspring. So, these minor changes add up and over millions of years new structures and proteins arise. Also, it is worth noting that nature usually uses previous proteins to build up new proteins (it does not create proteins from scratch), because lots of proteins share common domains and folds. I hope that helps!

[@KenJackson_US]

Bootlee, what you have just recited is the dogma believed by the religion of Darwinism. The problem with this dogma is that new proteins CAN'T be built up step by step because they don't give any advantage at all until they're complete and correct. Proteins are totally dependent on their shape to do their job and the shape is totally dependent on the precise sequence of amino acids that comprise them. You can't get there a little at a time. Even if you start with an existing protein, there's no straightforward mutation path to get to another. The field of possible intermediate steps is too big to comprehend. As I mentioned, it's 10^130 for even a small protein. That's not a probability, it's the number of possible sequences. Remember the "correct" amino acids are just as likely to mutate as the "incorrect" ones. Any random random walk from functioning protein to functioning protein would take trillions of years during which there would be no functioning protein to fill the need.

[@woodbmx213]

I see what you mean, but nature reuses a lot of protein domains in various different proteins. I agree that protein dynamics, folding, de novo engineering does not answer all the questions yet, but do you have a better hypothesis to explain this phenomena?

[@Mark16v15]

Someone help me out here. If this scientists says he can design a protein by first designing the right DNA sequence to create it, but if some theologian agrees that sounds logical, and thus suggests that the first proteins (i.e., making up the first life) must have also required some great intelligence to design them (i.e., intelligent design), the man of God is considered an ignorant uneducated unscientific illiterate religious nutcase. How come he can teach intelligent design in the classroom, but such is forbidden to others?

[@AntonOresten]

and he's not even a real baker.. wow... grrr