Title

Full length amylin oligomer aggregation: insights from molecular dynamics simulations and implications for design of aggregation inhibitors

Authors

Authors

W. M. Berhanu;A. E. Masunov

Comments

Authors: contact us about adding a copy of your work at STARS@ucf.edu

Abbreviated Journal Title

J. Biomol. Struct. Dyn.

Keywords

critical nucleation; lag phase; cross seeding; oligomer; amylin; MM-PBSA; free energy; cluster analysis; secondary structure; RMSD; RMSF; pramlintide; ISLET AMYLOID POLYPEPTIDE; SOLID-STATE NMR; A-BETA; ELECTRON-MICROSCOPY; A-BETA-42 PEPTIDE; ATOMIC STRUCTURES; FIBRILS; ALZHEIMERS; IAPP; MECHANISM; Biochemistry & Molecular Biology; Biophysics

Abstract

Amyloid oligomers are considered to play essential roles in the pathogenesis of amyloid-related degenerative diseases including type 2 diabetes. Using an explicit solvent all atomic MD simulation, we explored the stability, conformational dynamics and association force of different single-layer models of the full-length wild-type and glycine mutants of amylin (pentamer) obtained from a recent high resolution fibril model. The RMSF profile shows enhanced flexibility in the disorder (Lys1-Cys7) and turn region (Ser19-Gly23), along with smallest fluctuation at the residues (Asn14-Phe15Leu16-Val17-His18) of beta(1) region and (Ala25-Ile26-Leu27-Ser28-Ser29) of the beta(2) region. We obtained a significant difference in backbone RMSD between the wild-type and the mutants, indicating that mutations affected the stability of the peptide. The RMSD and RMSF profiles indicate the edge and loop residues are the primary contributors to the overall conformational changes. The degree of structural similarity between the oligomers in the simulation and the fibril conformation is proposed as the possible explanation for experimentally observed shortening of the nucleation lag phase of amylin with oligomer seeding. On the basis of structure-stability findings, the beta(1) and beta(2) portions are optimal target for further anti-amyloid drug design. The MM-PBSA binding energy calculation reveals the binding of amylin: amylin strands in single layer is dominated by contributions from van der Waals interactions. The non-polar solvation term is also found to be favorable. While the electrostatic interactions and polar solvation energy was found to be favorable for the interaction for the larger aggregate and unfavorable for the smaller aggregates. A per-residue decomposition of the binding free energy has been performed to identify the residues contributing most to the self-association free energy. Residues found in the beta-sheet regions were found to be key residue making the largest favorable contributions to the single-layer association. The result from our simulation could be used in rational design of new amylinomimetic agent, amylin aggregation inhibitors and amylin-specific biomarkers.

Journal Title

Journal of Biomolecular Structure & Dynamics

Volume

32

Issue/Number

10

Publication Date

1-1-2014

Document Type

Article

Language

English

First Page

1651

Last Page

1669

WOS Identifier

WOS:000340120600012

ISSN

0739-1102

Share

COinS