Douglas Renfrew, Ph.D.

As an undergraduate, P. Douglas Renfrew fell in love with protein structure while working in the laboratory of Sylvie Doublié at the University of Vermont. He continued doing protein structure research with Brian Kuhlman at the University of North Carolina at Chapel Hill where his work focused on the incorporation and use of non-canonical amino acids (NCAAs) into the Rosetta Macromolecular Modeling Suite. Renfrew expanded on this work as a postdoctoral researcher at New York University, where he focused on adapting tools developed for protein design to work with several classes of protein-like molecules called foldamers.

He came to the Simons Foundation in 2014 to work on protein and foldamer design, and protein structure and function determination with the Systems Biology Group at the Center for Computational Biology. The structures of NCAA side chains and foldamer chemistries allow them to explore conformations and interactions inaccessible to peptides made from only the 20 canonical amino acids. Additionally, classes of NCAAs and foldamers have other desirable properties such as resistance to proteolysis, ease of synthesis, or the ability to function in non-biological solvents. Using NCAAs and/or foldamers during a design simulation has allowed researchers to design tighter protein-protein interactions. His 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. With Vikram Mulligan, Renfrew is the co-head of the Biomolecular Design Group.

Renfrew studies 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.

Education

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