title: Genetic Algorithm Managed Peptide Mutant Screening: Optimizing Peptide Ligands for Targeted Receptor Binding.
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 α3β2-nicotinic acetylcholine receptor (nAChR) isoform. A series of top resulting peptide ligands with high sequence homology was obtained, with each mutant having an estimated ΔGbindapproximately 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 α3β2-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.
authors.affiliation: Department of Chemistry and Biochemistry and ‡Department of Computer Science, Boise State University , 1910 University Drive, Boise, Idaho 83725, United States.
authors.forename: Matthew D
authors.initials: MD
authors.lastname: King
authors.affiliation: Department of Chemistry and Biochemistry and ‡Department of Computer Science, Boise State University , 1910 University Drive, Boise, Idaho 83725, United States.
authors.forename: Thomas
authors.initials: T
authors.lastname: Long
authors.affiliation: Department of Chemistry and Biochemistry and ‡Department of Computer Science, Boise State University , 1910 University Drive, Boise, Idaho 83725, United States.
authors.forename: Timothy
authors.initials: T
authors.lastname: Andersen
authors.affiliation: Department of Chemistry and Biochemistry and ‡Department of Computer Science, Boise State University , 1910 University Drive, Boise, Idaho 83725, United States.
authors.forename: Owen M
authors.identifier: 0000-0002-1502-3462
authors.initials: OM
authors.lastname: McDougal
mesh_terms: D000465:Algorithms; D000595:Amino Acid Sequence; D000818:Animals; D020916:Conotoxins / Q000737:chemistry / Q000235:genetics / Q000494:pharmacology*; D055808:Drug Discovery; D006801:Humans; D008958:Models, Molecular; D009154:Mutation; D018733:Nicotinic Antagonists / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D019151:Peptide Library; D011485:Protein Binding; D051381:Rats; D011978:Receptors, Nicotinic / Q000378:metabolism*; D012984:Software
chemical_list: D020916:Conotoxins; D018733:Nicotinic Antagonists; D019151:Peptide Library; D011978:Receptors, Nicotinic; C098872:alpha-conotoxin MII; C419362:nicotinic receptor alpha3beta2