Mutation Sensitivity Maps: Identifying Residue Substitutions That Impact Protein Structure Via a Rigidity Analysis In Silico Mutation Approach.

Understanding how an amino acid substitution affects a protein's structure can aid in the design of pharmaceutical drugs that aim at countering diseases caused by protein mutants. Unfortunately, performing even a few amino acid substitutions in vitro is both time and cost prohibitive, whereas an exhaustive analysis that involves systematically mutating all amino acids in the physical protein is infeasible. Computational methods have been developed to predict the effects of mutations, but even many of them are computationally intensive or are else dependent on homology or experimental data that may not be available for the protein being studied. In this work, we motivate and present a computation pipeline whose only input is a Protein Data Bank file containing the 3D coordinates of the atoms of a biomolecule. Our high-throughput approach uses our ProMuteHT algorithm to exhaustively generate in silico amino acid substitutions at each residue, and it also includes an energy minimization option. This is in contrast to our previous work, where we analyzed the effects of in silico mutations to Alanine, Serine, and Glycine only. We exploit the speed of a fast rigidity analysis approach to analyze our protein variants, and develop a Mutation Sensitivity (MuSe) Map, to permit identifying residues that are most sensitive to mutations. We present a case study to show the degree to which a MuSe Map and whisker plots are able to locate amino acids whose mutations most affect a protein's structure as inferred from a rigidity analysis approach.