title: Conformation preorganization: effects of S20G mutation on the structure of human islet amyloid polypeptide segment.
abstract: The missense mutation S20G in the human islet amyloid polypeptide (hIAPP) is supposed to be associated with the early onset of type II diabetes (T2DM) in Asian population. How such a single-point mutation induces variation of the conformation distribution and the amyloidogenic properties of hIAPP is still unknown. We studied the conformational ensembles of hIAPP segment 15-27 in both wild type and the S20G mutant type by performing extensive replica exchange molecular dynamics simulations in explicit solvent model. Our results reveal that the residue G20 initiates a turnlike structure in the neighborhood, facilitating the formation of long-ranged contacts. Moreover, we find that the point mutation favors protofibril model of full length hIAPP suggested recently based on experimental measurements. Such a conformational preorganization will decrease the entropy cost during the process of peptide self-assembly, which is a possible explanation of the faster fibrillation of hIAPP S20G mutant than that of the wild type found by experiments.
authors.affiliation: School of Biological Sciences, Nanyang Technological University, Singapore 637551.
authors.forename: Weixin
authors.initials: W
authors.lastname: Xu
authors.forename: Ping
authors.initials: P
authors.lastname: Jiang
authors.forename: Yuguang
authors.initials: Y
authors.lastname: Mu
mesh_terms: D000682:Amyloid / Q000737:chemistry* / Q000235:genetics*; D006801:Humans; D058228:Islet Amyloid Polypeptide; D007700:Kinetics; D008958:Models, Molecular; D009154:Mutation; D010446:Peptide Fragments / Q000737:chemistry* / Q000235:genetics*; D011487:Protein Conformation; D013816:Thermodynamics
chemical_list: D000682:Amyloid; D058228:Islet Amyloid Polypeptide; D010446:Peptide Fragments