Genetic Algorithm Managed Peptide Mutant Screening: Optimizing Peptide Ligands for Targeted Receptor Binding

Overview

Journal J Chem Inf Model

Publisher American Chemical Society

Specialties Chemistry
Medical Informatics

Date 2016 Dec 28

PMID 28024403

Citations 7

Authors

Matthew D King

Thomas Long

Timothy Andersen

Owen M McDougal

Affiliations

Soon will be listed here.

Abstract

This study demonstrates the utility of genetic algorithms to search exceptionally large and otherwise intractable mutant libraries for sequences with optimal binding affinities for target receptors. The Genetic Algorithm Managed Peptide Mutant Screening (GAMPMS) program was used to search an α-conotoxin (α-CTx) MII mutant library of approximately 41 billion possible peptide sequences for those exhibiting the greatest binding affinity for the αβ-nicotinic acetylcholine receptor (nAChR) isoform. A series of top resulting peptide ligands with high sequence homology was obtained, with each mutant having an estimated ΔG approximately double that of the potent native α-CTx MII ligand. A consensus sequence from the top GAMPMS results was subjected to more rigorous binding free energy calculations by molecular dynamics and compared to α-CTx MII and other related variants for binding with αβ-nAChR. In this study, the efficiency of GAMPMS to substantially reduce the sample population size through evolutionary selection criteria to produce ligands with higher predicted binding affinity is demonstrated.

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