Amyloid-like fibrils are found in many fatal diseases, such as Alzheimer's disease, Parkinson's disease, type II diabetes mellitus, and prion diseases. Recently, the structural characterization of the MVGGVV peptide from the C-terminal hydrophobic segment of the amyloid-B (AB) peptide has revealed a general feature of amyloid-like fibrils, termed as "steric zipper", which is constituted by a tight side-chain complementation of the opposing B-sheet layers. In this study, several all-atom molecular dynamics simulations with explicit water were conducted to investigate the importance of steric zipper on the aggregation of the MVGGVV peptide. Our results show that the structural stability of the MVGGVV oligomers increases with increasing the number of B-strands. We further proposed that the octameric structure (the SH2-ST4 model in this study) is the possible nucleus seed for MVGGVV protofibril formation. Our results also demonstrated that hydrophobic interaction is the principle driving force to stabilize the adjacent B-strands while the steric zipper involved M1, V2, V5 and V6 is responsible for holding the neighboring B-sheet layers together. Finally, a twisted model of the MVGGVV assembly (SH2-ST50), based on the averaged twisted angle of approximately 11.5 degrees between the adjacent B-strands of the SH2-ST4 model, was proposed. Our results gain insights into the aggregation of the MVGGVV peptide in atomic details and may provide a hint for designing new inhibitors able to prevent the fibril formation of the AB peptide.
Download full-text PDF |
Source |
|---|---|
| http://dx.doi.org/10.1080/07391102.2010.10507342 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Inhibition of Aβ Amyloid Growth and Toxicity by Silybins: The Crucial Role of Stereochemistry.
ACS Chem Neurosci
August 2017
Institute of Biostructures and Bioimages-Catania, National Research Council, Via Paolo Gaifami 8, 95126 Catania, Italy.
The self-assembling of the amyloid β (Aβ) peptide into neurotoxic aggregates is considered a central event in the pathogenesis of Alzheimer's disease (AD). Based on the "amyloid hypothesis", many efforts have been devoted to designing molecules able to halt disease progression by inhibiting Aβ self-assembly. Here, we combine biophysical (ThT assays, TEM and AFM imaging), biochemical (WB and ESI-MS), and computational (all-atom molecular dynamics) techniques to investigate the capacity of four optically pure components of the natural product silymarin (silybin A, silybin B, 2,3-dehydrosilybin A, 2,3-dehydrosilybin B) to inhibit Aβ aggregation.
View Article and Find Full Text PDFImpact of sequence on the molecular assembly of short amyloid peptides.
Proteins
July 2014
Department of Chemical and Biomolecular Engineering, North Carolina State University, Raleigh, North Carolina, 27695-7905.
The goal of this work is to understand how the sequence of a protein affects the likelihood that it will form an amyloid fibril and the kinetics along the fibrillization pathway. The focus is on very short fragments of amyloid proteins since these play a role in the fibrillization of the parent protein and can form fibrils themselves. Discontinuous molecular dynamics simulations using the PRIME20 force field were performed of the aggregation of 48-peptide systems containing SNQNNF (PrP (170-175)), SSTSAA (RNaseA(15-20)), MVGGVV (Aβ(35-40)), GGVVIA (Aβ(37-42)), and MVGGVVIA (Aβ(35-42)).
View Article and Find Full Text PDFAlternative packing modes leading to amyloid polymorphism in five fragments studied with molecular dynamics.
Biopolymers
August 2012
University of Central Florida, Orlando, FL 32826, USA.
Amyloid aggregates have been implicated in the pathogenesis of diseases such as type 2 diabetes, Alzheimer's, Parkinson's, and prion disease. Recently determined microcrystal structures of several short peptide segments derived from fibril-forming proteins revealed coexistence of alternative aggregation modes (amyloid polymorphism) formed by the same segment. This polymorphism may help in understanding the influence of the side chain packing on the amyloid stability.
View Article and Find Full Text PDFCan molecular dynamics simulations assist in design of specific inhibitors and imaging agents of amyloid aggregation? Structure, stability and free energy predictions for amyloid oligomers of VQIVYK, MVGGVV and LYQLEN.
J Mol Model
October 2011
NanoScience Technology Center and Department of Chemistry, University of Central Florida, Orlando, FL 32826, USA.
The aggregation modes of hexapeptide fragments of Tau, Insulin and Aβ peptide (VQIVYK, MVGGVV and LYQLEN) were found from their microcrystalline structures that had been recently resolved by X-ray analysis. The atomic structures reveal a dry self-complementary interface between the neighboring β-sheet layers, termed "steric zipper". In this study we perform several all-atom molecular dynamics simulations with explicit water to analyze stability of the crystalline fragments of 2-10 hexapeptides each and their analogs with single glycine replacement mutations to investigate the structural stability, aggregation behavior and thermodynamic of the amyloid oligomers.
View Article and Find Full Text PDFThe importance of steric zipper on the aggregation of the MVGGVV peptide derived from the amyloid beta peptide.
J Biomol Struct Dyn
August 2010
Graduate Institute of Biotechnology National Taipei University of Technology, 1 Sec. 3 Zhong Xiao E. Rd., Taipei, Taiwan 10608.
Amyloid-like fibrils are found in many fatal diseases, such as Alzheimer's disease, Parkinson's disease, type II diabetes mellitus, and prion diseases. Recently, the structural characterization of the MVGGVV peptide from the C-terminal hydrophobic segment of the amyloid-B (AB) peptide has revealed a general feature of amyloid-like fibrils, termed as "steric zipper", which is constituted by a tight side-chain complementation of the opposing B-sheet layers. In this study, several all-atom molecular dynamics simulations with explicit water were conducted to investigate the importance of steric zipper on the aggregation of the MVGGVV peptide.
View Article and Find Full Text PDFWant AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!