title: Structural and functional restraints on the occurrence of single amino acid variations in human proteins.
abstract: Human genetic variation is the incarnation of diverse evolutionary history, which reflects both selectively advantageous and selectively neutral change. In this study, we catalogue structural and functional features of proteins that restrain genetic variation leading to single amino acid substitutions. Our variation dataset is divided into three categories: i) Mendelian disease-related variants, ii) neutral polymorphisms and iii) cancer somatic mutations. We characterize structural environments of the amino acid variants by the following properties: i) side-chain solvent accessibility, ii) main-chain secondary structure, and iii) hydrogen bonds from a side chain to a main chain or other side chains. To address functional restraints, amino acid substitutions in proteins are examined to see whether they are located at functionally important sites involved in protein-protein interactions, protein-ligand interactions or catalytic activity of enzymes. We also measure the likelihood of amino acid substitutions and the degree of residue conservation where variants occur. We show that various types of variants are under different degrees of structural and functional restraints, which affect their occurrence in human proteome.
authors.affiliation: Biocomputing Group, Department of Biochemistry, University of Cambridge, Cambridge, United Kingdom.
authors.forename: Sungsam
authors.initials: S
authors.lastname: Gong
authors.forename: Tom L
authors.initials: TL
authors.lastname: Blundell
mesh_terms: D019943:Amino Acid Substitution; D001665:Binding Sites; D030562:Databases, Protein; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D014644:Genetic Variation; D006801:Humans; D006860:Hydrogen Bonding; D008958:Models, Molecular; D009154:Mutation; D011110:Polymorphism, Genetic; D011485:Protein Binding; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D011506:Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D011506:Proteins