I. Introduction to Protein Design
II. Design of New Protein Functions
Part I: Introduction to Protein Design
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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 sequence. It is then possible to back translate to the DNA sequence and synthesize the gene that can then be 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.
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 http://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.
- David Baker iBioMagazine: Crowd Sourcing Science
- Susan Lindquist iBioEducation: Protein Folding and Disease
- Stephen Mayo iBioSeminar: Recent Advances in Computational Protein Design
- Rama Ranganathan iBioMagazine: Finding the ‘Effective Variables’ in Biological Systems
- William Shih iBioSeminar: Nanofabrication via Structural DNA
Tinberg CE, Khare SD, Dou J, Doyle L, Nelson JW, Schena A, Jankowski W, Kalodimos CG, Johnsson K, Stoddard BL, Baker D. Computational design of ligand-binding proteins with high affinity and selectivity. Nature. 2013 Sep 12;501(7466):212-6. PMID:24005320
King NP, Sheffler W, Sawaya MR, Vollmar BS, Sumida JP, André I, Gonen T, Yeates TO, Baker D. Computational design of self-assembling protein nanomaterials with atomic level accuracy. Science. 2012 Jun 1;336(6085):1171-4. PMID:22654060
Fleishman SJ, Whitehead TA, Ekiert DC, Dreyfus C, Corn JE, Strauch EM, Wilson IA, Baker D. Computational design of proteins targeting the conserved stem region of influenza hemagglutinin. Science. 2011 May 13;332(6031):816-21. PMID:21566186
Whitehead TA, Chevalier A, Song Y, Dreyfus C, Fleishman SJ, De Mattos C, Myers CA, Kamisetty H, Blair P, Wilson IA, Baker D. Optimization of affinity, specificity and function of designed influenza inhibitors using deep sequencing. Nat Biotechnol. 2012 May 27;30(6):543-8. PMID:22634563
Koga N, Tatsumi-Koga R, Liu G, Xiao R, Acton TB, Montelione GT, Baker D. Principles for designing ideal protein structures. Nature. 2012 Nov 8;491(7423):222-7. PMID: 23135467
Foldit Publications: http://fold.it/portal/info/science#folditpub
Rosetta@Home information: http://boinc.bakerlab.org/