- First Name
- Last Name
- Current Position
- Senior Fellow
I am a senior fellow in the Baker lab. I received my BE in Chemical Engineering and Mathematics from Vanderbilt University in 2001. After a stint designing groundwater remediation plants with Arcadis GE, I matriculated to Berkeley and received my PhD under Doug Clark in the Dept of Chemical Engineering. Starting this fall, I will be an Assistant Professor in the Chemical Engineering and Materials Science Department at Michigan State University, where I will continue the design and construction of functional proteins. My group will develop and maintain particular expertise in the design and engineering of new protein-protein and protein-analyte interactions using an amalgam of elegant experiments coupled to computational modeling and design. Success in these areas will drive progress in the conversion of biomass to fuels and commodity chemicals by microbial fermentation.
Proteins bind to and interact with other proteins or small molecules. Such communications drive much of cellular physiology including cellular signaling, metabolic pathways, and the immune response. While an extensive literature exists on the construction of proteins to bind other molecules1-3 (e.g. antibodies), important open questions remain about the limits of specificity and affinity garnered by such engineering approaches.
For my postdoctoral research, I have addressed whether our knowledge of the various forces that hold dissociable protein complexes together is sufficient to design de novo proteins that can bind an arbitrary target. This question is a grand challenge in molecular biology; success would show that we could traverse the gulf that separates the conception of the function of a protein to its primary sequence. Starting from the hypothesis that protein interactions are dominated by only a handful of energetically important residues, our protein-interaction subgroup developed a computational methodology to harbor such regions in unrelated proteins4. I then developed a yeast display assay to test binding of our designs as well as evolve the more promising variants into tighter binders.
For the initial trial I targeted a conserved region on the important protein hemagglutinin (HA) from the Influenza A virus, as antibodies that bind in this region may not be economically viable as therapeutics5-6. Two different proteins were designed that hit this conserved HA region, and binding of each was readily matured to affinities that rival the antibodies. The mutations that improve the designs can be explained by deficiencies in the modeling of electrostatics and solvation of polar or charged groups, and suggests routes for clear improvement in our conception of protein interfaces. Most importantly, a crystal structure of one of the HA-design complexes was solved, validating our design at the atomic level7.
I remain interested in developing experimental methods that can efficiently search through protein functional sequence space. Such simple methods would complement rational and directed evolution approaches in the engineering of proteins with a desired function. In a non-thesis project at Berkeley, I developed a strategy to increase recombinant protein production through a subtle reconfiguring of protein folding pathways8. For my current project I have been working with Aaron Chevalier to develop a method to assess the binding and thermodynamic folding energies of all possible single point mutations in a protein sequence through the enabling technologies of synthetic DNA libraries, yeast surface display, and deep sequencing. This method will help resolve questions on the nature of the fitness landscape of protein sequences, to elucidate functionally and structurally important regions of the interrogated protein, as well as be used to rapidly evolve proteins through the nature of the additive (non-epistatic) nature of protein sequence/functional space.
 Zahnd C, Amstutz P, Pluckthun A. (2007), Nature Methods 4, 269.
 Chao G, Lau WL, Hackel BJ, Sazinsky SL, Lippow SM, Wittrup KD. (2006), Nat Protoc. 1:755.
 Mazor Y, Van Blarcom T, Iverson BL, Georgiou G. (2008), Nat Protoc. 3:1766.
 Fleishman SJ, Corn JE, Strauch EM, Whitehead TA, Baker D (2010), in preparation
 Ekiert DC, Bhabha G, Elsliger MA, Friesen RH, Jongeneelen M, Throsby M, Goudsmit J, Wilson IA. (2009), Science 324:246.
 Sui J, Hwang WC, Perez S, Wei G, Aird D, Chen LM, Santelli E, Stec B, Cadwell G, Ali M, Wan H, Murakami A, Yammanuru A, Han T, Cox NJ, Bankston LA, Donis RO, Liddington RC, Marasco WA. (2009), Nat Struct Mol Biol. 16:265.
 Fleishman SJ*, Whitehead TA*, Ekiert D*, Dreyfus C, Corn JE, Strauch EM, Wilson IA, Baker D (2010), accepted by Science
*joint 1st authors
 Whitehead TA, Bergeron LM, Clark DS (2009), Protein Eng Des Sel 22:607.
- Member for
- 2 years 36 weeks