The computational design of protein-ligand interfaces

Abstract

ANDREW MORIN

Dissertation under the direction of Professor Jens Meiler.

Interaction between protein and ligand is a fundamental mechanism in biology. The goal of my dissertation research was to develop a general and repeatable method for designing protein interfaces to small-molecule and peptide ligands using in silico, rational design techniques. Establishing a robust computational method for designing protein-ligand interactions would have broad application in both basic science and the development of protein therapeutics to address disease. The D-ala-D-ala peptide target of the glycopeptide antibiotic vancomycin was chosen as proof-of-concept interface system. Using the ROSETTA protein design program, I attempted to create novel protein interfaces capable of binding the D-ala peptide. Although low affinity interactions were observed for some ROSETTA designed proteins, no high affinity peptide binding proteins were achieved. Subsequent experimental and computational analysis revealed key contributors to the lack of design success. Taken as a whole, the results obtained in the course of my dissertation research offer insights into the strengths and weaknesses of computational ligand-interface design methods and the structural and biophysical characteristics of protein-ligand interfaces.