title: Alpha Helices Are More Robust to Mutations than Beta Strands.
abstract: The rapidly increasing amount of data on human genetic variation has resulted in a growing demand to identify pathogenic mutations computationally, as their experimental validation is currently beyond reach. Here we show that alpha helices and beta strands differ significantly in their ability to tolerate mutations: helices can accumulate more mutations than strands without change, due to the higher numbers of inter-residue contacts in helices. This results in two patterns: a) the same number of mutations causes less structural change in helices than in strands; b) helices diverge more rapidly in sequence than strands within the same domains. Additionally, both helices and strands are significantly more robust than coils. Based on this observation we show that human missense mutations that change secondary structure are more likely to be pathogenic than those that do not. Moreover, inclusion of predicted secondary structure changes shows significant utility for improving upon state-of-the-art pathogenicity predictions.
authors.affiliation: MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Crewe Road, Edinburgh EH4 2XU, United Kingdom.|Institute of Biochemistry, Biological Research Centre of the Hungarian Academy of Sciences, Szeged, Temesvári krt. 62, Hungary.
authors.forename: György
authors.initials: G
authors.lastname: Abrusán
authors.affiliation: MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Crewe Road, Edinburgh EH4 2XU, United Kingdom.
authors.forename: Joseph A
authors.identifier: 0000-0003-4132-0628
authors.initials: JA
authors.lastname: Marsh
mesh_terms: D000595:Amino Acid Sequence; D019295:Computational Biology; D006801:Humans; D008958:Models, Molecular; D009154:Mutation; D000072756:Protein Conformation, alpha-Helical; D000072757:Protein Conformation, beta-Strand; D020539:Sequence Analysis, Protein