Methods and applications in computational protein design

Abstract

In this thesis, we summarize our work on applications and methods for computational protein design. First, we apply computational protein design to address the problem of degradation in stored proteins. Specifically, we target cysteine, asparagine, glutamine, and methionine amino acid residues to reduce or eliminate a protein's susceptibility to degradation via aggregation, deamidation, and oxidation. We demonstrate this technique on a subset of degradation-prone amino acids in phosphotriesterase, an enzyme that hydrolyzes toxic organophosphates including pesticides and chemical warfare agents. Second, we introduce BroMAP/A*, an exhaustive branch-and- bound search technique with enumeration. We compare performance of BroMAP/A* to DEE/A*, the current standard for conformational search with enumeration in the protein design community. When limited computational resources are available, DEE/A* sometimes fails to find the global minimum energy conformation and/or enumerate the lowest-energy conformations for large designs. Given the same computational resources, we show how BroMAP/A* is able to solve large designs by efficiently dividing the search space into small, solvable subproblems.