Baker, D. (2015, July 16). Prediction and design of protein structures and interactions [Video file]. In The Biomedical & Life Sciences Collection, Henry Stewart Talks. Retrieved February 22, 2024, from https://hstalks.com/bs/446/.
Export Citation (RIS)
Published on October 1, 2007
Reviewed on July 16, 2015
Prof. David Baker has not informed HSTalks of any commercial/financial relationship that it is appropriate to disclose.
Please wait while the transcript is being prepared...
Structural biology should be computable.It's been known for over 40 years thatprotein structures are completely determined by their amino acid sequences.For almost all protein structures and all protein-protein complexes,the experimentally observed structures andconformations are almost certain to correspond to global free energy minima.So, it should be possible to predict the structures of proteins andprotein-protein complexes readily byidentifying the global free energy minima for a polypeptide chain,in case of protein structure prediction,or identifying the global free energy minima for two proteins coming together,which will be the prediction of protein complexes problem.If we could do this, it would both be a fundamental test ofour understanding of macromolecular and interactions,and it would also be huge practical relevance asthe cost of determining protein structures computationally,would be a small fraction of the cost ofcurrent experimental methods such as X-ray crystallography, and NMR spectroscopy.But, as you know, today,structural biology is not computed,it is primarily experimental science.And what I'm going to tell you about today is progresstowards making structural biology computable.
The work I'm going to tell you about today is carried outwith a computer program being developed in my group,and groups of people left my group inthe last seven years that has the following structure.We have a model of the energetics of inter and intramolecular interactions,which allows us to compute the energy ofconformation of a protein or a protein- protein complex.And given that model,we can do one of two things.We can either do a prediction problem,in which we're given for example,the sequence of a protein and asked to findthe lowest energy structure for that sequence,that would correspond to the Ab initio structure prediction problem.We can also take the structures of two proteins,and try and find the lowest energy docked arrangement,that would be the protein-protein docking problem.In these cases, we're given the sequence orthe structures and trying to find the lowest energy conformation.Now, the inverse problem is the design problem,where we're given a structure and we want to find the lowest energy sequence.So for example, that would be the problem designing a new protein structure,a sequence that would fold to give a new structure or the problem ofgiven a protein-protein complex designing an interface between the two proteins,which will allow them to bind to each other tightly.This approach has been extended to protein ligand interactions.So for example, ligand docking,the design of new enzymes and to protein DNA interactions.In particular, the design of new DNA binding proteins with new specificities,which is something that we've had a fair amount of success with lately.However in this lecture, I'm going to focus on the prediction and design ofprotein structure and protein-protein interactions.