Premium
Structural stability and aggregation behavior of the VEALYL peptide derived from human insulin: A molecular dynamics simulation study
Author(s) -
Lin YehFon,
Zhao JianHua,
Liu HsuanLiang,
Liu KungTien,
Chen JennTzong,
Tsai WeiBor,
Ho Yih
Publication year - 2009
Publication title -
peptide science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.556
H-Index - 125
eISSN - 1097-0282
pISSN - 0006-3525
DOI - 10.1002/bip.21322
Subject(s) - zipper , chemistry , steric effects , molecular dynamics , oligomer , peptide , side chain , fibril , hydrophobic effect , biophysics , structural stability , crystallography , stereochemistry , biochemistry , computational chemistry , organic chemistry , structural engineering , algorithm , computer science , engineering , biology , polymer
The VEALYL peptide from B chain (residues 12–17) of insulin has been shown to form amyloid‐like fibrils. Recently, the atomic structure of the VEALYL oligomer has been determined by X‐ray microcrystallography and reveals a dry, tightly self‐complementing structure between the neighboring β‐sheet layers, termed as “steric zipper.” In this study, several molecular dynamics simulations with all‐atom explicit water were conducted to investigate the structural stability and aggregation behavior of the VEALYL peptide with various sizes and its single glycine replacement mutations. The results of our single‐layer models showed that the structural stability of the VEALYL oligomers increases significantly with increasing the number of β‐strands. We further suggested that the minimal nucleus seed for VEALYL fibril formation could be as small as three or four peptides. Our results also revealed that the hydrophobic interaction between E2 and Y5 plays an important role in stabilizing the adjacent β‐strands within the same layer, whereas the hydrophobic steric zipper formed via the side chains of V1, A3, L4, Y5, and L6 locks the two neighboring β‐sheet layers together. Mutation simulations showed that the substitution of a single glycine residue directly disrupts this steric zipper, resulting in the destabilization of the VEALYL oligomers. This study provides the atomic insights into understanding the aggregation behavior of the VEALYL peptide. It may also be helpful for designing new or modified capping peptides able to break the driving force for aggregation and to prevent the fibril formation of the VEALYL peptide and the insulin protein. © 2010 Wiley Periodicals, Inc. Biopolymers (Pept Sci) 94: 269–278, 2010. This article was originally published online as an accepted preprint. The “Published Online” date corresponds to the preprint version. You can request a copy of the preprint by emailing the Biopolymers editorial office at biopolymers@wiley.com