title: Rational design of temperature-sensitive alleles using computational structure prediction.
abstract: Temperature-sensitive (ts) mutations are mutations that exhibit a mutant phenotype at high or low temperatures and a wild-type phenotype at normal temperature. Temperature-sensitive mutants are valuable tools for geneticists, particularly in the study of essential genes. However, finding ts mutations typically relies on generating and screening many thousands of mutations, which is an expensive and labor-intensive process. Here we describe an in silico method that uses Rosetta and machine learning techniques to predict a highly accurate "top 5" list of ts mutations given the structure of a protein of interest. Rosetta is a protein structure prediction and design code, used here to model and score how proteins accommodate point mutations with side-chain and backbone movements. We show that integrating Rosetta relax-derived features with sequence-based features results in accurate temperature-sensitive mutation predictions.
authors.affiliation: Department of Biology, Center for Genomics and Systems Biology, New York University, New York, New York, United States of America.
authors.forename: Christopher S
authors.initials: CS
authors.lastname: Poultney
authors.forename: Glenn L
authors.initials: GL
authors.lastname: Butterfoss
authors.forename: Michelle R
authors.initials: MR
authors.lastname: Gutwein
authors.forename: Kevin
authors.initials: K
authors.lastname: Drew
authors.forename: David
authors.initials: D
authors.lastname: Gresham
authors.forename: Kristin C
authors.initials: KC
authors.lastname: Gunsalus
authors.forename: Dennis E
authors.initials: DE
authors.lastname: Shasha
authors.forename: Richard
authors.initials: R
authors.lastname: Bonneau
mesh_terms: D000483:Alleles; D001185:Artificial Intelligence; D019295:Computational Biology / Q000379:methods*; D008958:Models, Molecular; D009154:Mutation; D011487:Protein Conformation; D011506:Proteins / Q000737:chemistry* / Q000235:genetics*; D013696:Temperature
chemical_list: D011506:Proteins