title: Free energy simulations of amylin I26P mutation in a lipid bilayer.
abstract: The amylin peptide in a dioleoylphosphatidylcholine (DOPC) bilayer is studied using united atom molecular dynamics (MD) simulations. Dynamics and transport properties of the peptide and the phospholipid bilayer are investigated. The lateral diffusion of DOPC is in the order of 10(-8) cm(2) s(-1), which is in agreement with the experimental results. The order parameter and density profile for phospholipid molecules in the bilayer are calculated. The secondary structure of amylin peptide shows that the amino acids in two terminals are structureless and two α-helical segments in the peptide are connected through an unstructured link. This structure is similar to the experimental structure in the membrane-mimicking media. Free energy calculations of the Ile26 → Pro mutation in the amylin peptide are performed in the bilayer and in aqueous solution using molecular dynamics simulations and a thermodynamic cycle. It is shown that in the mutated peptide in aqueous solution, the α-helix structure changes to a 5-helix, whereas this configuration is preserved in the bilayer environment. It is interesting that the accessible surface area increases for hydrophobic residues in the bilayer and for hydrophilic residues in aqueous solution as the coupling parameter changes from 0 to 1. These results are significant to understanding the aggregation mechanism of human amylin monomers in membranes to the dimers, trimers, oligomers, and fibrils associated with the type 2 diabetes at the atomic level.
authors.affiliation: Department of Chemistry, K.N. Toosi University of Technology, P.O. Box 15875-4416, Tehran, Iran.
authors.forename: Seifollah
authors.initials: S
authors.lastname: Jalili
authors.forename: Afsaneh
authors.initials: A
authors.lastname: Maleki
authors.forename: Mojdeh
authors.initials: M
authors.lastname: Akhavan
authors.forename: Bijan
authors.initials: B
authors.lastname: Najafi
authors.forename: Jeremy
authors.initials: J
authors.lastname: Schofield
mesh_terms: D000595:Amino Acid Sequence; D006801:Humans; D058228:Islet Amyloid Polypeptide / Q000737:chemistry* / Q000235:genetics; D008051:Lipid Bilayers / Q000737:chemistry*; D056004:Molecular Dynamics Simulation; D008969:Molecular Sequence Data; D020125:Mutation, Missense
chemical_list: D058228:Islet Amyloid Polypeptide; D008051:Lipid Bilayers