P. Douglas Renfrew


P. Douglas Renfrew

Research Interests

I study the three-dimensional structure of natural and unnatural macromolecules and complexes. The present focus of my research is twofold: to adapt the current tools of computational protein design to create functional molecules (be they traditional proteins or not), and to identify new protein-protein interactions.

The structures of noncanonical amino acid (NCAA) side chains and noncanonical backbone (NCBB, aka “foldamer”) chemistries allow them to explore conformations and interactions inaccessible to the 20 canonical amino acids. Additionally, classes of NCAAs and NCBBs have other desirable properties such as resistance to proteolysis, ease of synthesis, or the ability to function in nonbiological solvents. I have approached my first research aim by incorporating the ability to design NCAA side chains and NCBBs into the computational protein design program, Rosetta. Using NCAAs and/or NCBBs during a design simulation has allowed us to design tighter protein-protein interactions. This research has taken macromolecular design in a new direction and has enabled the development of novel protein interactions, protein-like therapeutics, and enzymes with increased stability.

Designing molecules to disrupt protein-protein interactions is only half of the puzzle. Chemical cross-linking of interacting proteins paired with protein sequencing via mass spectrometry (XL/MS) is a powerful technique that can be used to identify sets of interacting proteins and can also provide insight into the three-dimensional structure of those complexes in the form of distance constraints on pairs of interacting residues that can be used in protein structure prediction or homology modeling. In collaboration with the Nudler Lab at the New York University School of Medicine, I have been using this experimental information to guide computational modeling of the docked conformation of entire macromolecular ensembles, which can yield mechanistic insights that might otherwise be difficult or impossible to obtain directly through experimental techniques.

My Google Scholar profile can be found here.


Ph.D., Biochemistry and Biophysics (2009)

University of North Carolina at Chapel Hill, Chapel Hill, NC

B.S., Molecular Genetics, with Minors in Chemistry and Computer Science (2003)

University of Vermont, Burlington, VT

Selected Publications

Butterfoss GL, Renfrew PD, Kuhlman B, Kirshenbaum K, Bonneau R. A preliminary survey of the peptoid folding landscape. J Am Chem Soc. 2009;131(46):16798-16807. doi:10.1021/ja905267k.

Drew K, Renfrew PD, Craven TW, et al. Adding diverse noncanonical backbones to Rosetta: enabling peptidomimetic design. PLoS One. 2013;8(7):e67051. doi:10.1371/journal.pone.0067051.

Leaver-Fay A, Tyka M, Lewis SM., Lange, OF, Thompson J, Jacak R, Kaufman KW, Renfrew PD, Smith CA, Sheffler W, Davis IW, Cooper S, Treuille A, Mandell DJ, Richter F, Ban Y-EA, Fleishman SJ, Corn JE, Kim DE, Lyskov S, Berrondo M, Mentzer S, Popović Z, Havranek JJ, Karanicolas J, Das R, Meiler J, Kortemme T, Gray JJ, Kuhlman B, Baker D, Bradley P. Rosetta3: an object-oriented software suite for the simulation and design of macromolecules.” In: Simon M, ed. Computer Methods, Part C. San Diego, CA: Academic Press; 2011. Methods in Enzymology; vol. 487:545-574.

Renfrew PD, Choi EJ, Bonneau R, Kuhlman B. Incorporation of noncanonical amino acids into Rosetta and use in computational protein-peptide interface design. PLoS One. 2012;7(3):e32637. doi:10.1371/journal.pone.0032637.

Renfrew PD, Craven TW, Butterfoss GL, Kirshenbaum K, Bonneau R. A rotamer library to enable modeling and design of peptoid foldamers. J Am Chem Soc. 2014;136(24):8772-8782. doi:10.1021/ja503776z.

Yang C-Y, Renfrew PD, Olsen AJ, Zhang M, Yuvienco C, Bonneau R, Montclare JK. Improved stability and half-life of fluorinated phosphotriesterase using Rosetta. Chembiochem. 2014;15(12):1761-1764. doi:10.1002/cbic.201402062.