Title

Controlling The Aggregation And Rate Of Release In Order To Improve Insulin Formulation: Molecular Dynamics Study Of Full-Length Insulin Amyloid Oligomer Models

Keywords

β sheet; Aggregation; Amylin; Amyloid fibril; Binding free energy; Cross-β structure; Hydrogen bond; MM-PBSA; Molecular dynamic simulation; NNFGAIL; Oligomer; Secondary structure

Abstract

Most proteins do not aggregate while in their native functional states. However, they may be disturbed from their native conformation by certain change in the environment, and form unwanted oligomeric or polymeric aggregates. Recent experimental data demonstrate that soluble oligomers of amyloidogenic proteins are responsible for amyloidosis and its cytotoxicity. Human islet amyloid polypeptide (IAPP or amylin) is a 37-residue hormone found as fibrillar deposits in pancreatic extracts of nearly all type II diabetics. In this study we performed in silico mutation analysis to examine the stability of the double layer five strand aggregates formed by heptapeptide NNFGAIL segment from amyline peptide. This segment is one of the shortest fragments that can form amyloid fibrils similar to those formed by the full length peptide. The mutants obtained by single glycine replacement were also studied to investigate the specificity of the dry selfcomplementary interface between the neighboring β-sheet layers. The molecular dynamics simulations of the aggregates run for 20 ns at 330 K, the degree of the aggregate disassembly was investigated using several geometry analysis tools: the root mean square deviations of the C α atoms, root mean square fluctuations per residue, twist angles, interstrand distances, fraction of the secondary structure elements, and number of H-bonds. The analysis shows that most mutations make the aggregates unstable, and their stabilities were dependent to a large extent on the position of replaced residues. Our mutational simulations are in agreement with the pervious experimental observations. We also used free binding energy calculations to determine the role of different components: nonpolar effects, electrostatics and entropy in binding. Nonpolar effects remained consistently more favorable in wild type and mutants reinforcing the importance of hydrophobic effects in protein-protein binding. While entropy systematically opposed binding in all cases, there was no clear trend in the entropy difference between wildtype and glycine mutants. Free energy decomposition shows residues situated at the interface were found to make favorable contributions to the peptide-peptide association. The study of the wild type and mutants in an explicit solvent could provide valuable insight into the future computer guided design efforts for the amyloid aggregation inhibitor. © Springer-Verlag 2011.

Publication Date

3-1-2012

Publication Title

Journal of Molecular Modeling

Volume

18

Issue

3

Number of Pages

1129-1142

Document Type

Article

Personal Identifier

scopus

DOI Link

https://doi.org/10.1007/s00894-011-1123-3

Socpus ID

84861333269 (Scopus)

Source API URL

https://api.elsevier.com/content/abstract/scopus_id/84861333269

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