ProMuteHT: A High Throughput Compute Pipeline for Generating Protein Mutants in silico

TLDR: ProMuteHT is presented, a program for high throughput in silico generating user-specified sets of mutant protein structures with single or multiple amino acid substitutions that are of high quality, as determined via all-atom and mutated residue RMSD measurements for existing mutant structures in the PDB.

Abstract: Understanding how an amino acid substitution affects a protein's structure is fundamental to advancing drug design and protein docking studies. Mutagenesis experiments on physical proteins provide a precise assessment of the effects of mutations, but they are time and cost prohibitive. Computational approaches for performing in silico amino acid substitutions are available, but they are not suited for generating large numbers of protein variants needed for high-throughput screening studies. We present ProMuteHT, a program for high throughput in silico generating user-specified sets of mutant protein structures with single or multiple amino acid substitutions. We combine our custom mutation algorithm with side chain homology modeling external libraries, and generate energetically feasible mutant structures. Our efficient command-line invocation syntax requires only a few arguments to specify large datasets of mutant structures. We achieve quick run-times due to our hybrid approach in which we limit the use of costly energy calculations when mutating from a large to a small amino acid. We compare our mutant structures with those generated by FoldX, and report faster run-times. We show that the mutants generated by ProMuteHT are of high quality, as determined via all-atom and mutated residue RMSD measurements for existing mutant structures in the PDB.