Side chain interactions can impede amyloid fibril growth: replica exchange simulations of Abeta peptide mutant.
Using replica exchange molecular dynamics, we study the effect of Asp23Tyr mutation on Abeta(10-40) fibril growth. The effect of this mutation is revealed through the computation of free energy landscapes, the distributions of peptide-fibril interactions, and by comparison with the wild-type Abeta(10-40) peptide. Asp23Tyr mutation has a relatively minor influence on the docking of Abeta peptides to the fibril. However, it has a strong impact on the locking stage due to profound stabilization of the parallel in-registry beta-sheets formed by the peptides on the fibril edge. The enhanced stability of parallel beta-sheets results from the deletion of side chain interactions formed by Asp23, which are incompatible with the fibril-like conformers. Consequently, Asp23Tyr mutation is expected to promote fibril growth. We argue that strong off-registry side chain interactions may slow down fibril assembly as it occurs for the wild-type Abeta peptide. The analysis of experimental data offers support to our in silico conclusions.
Takeda
Takako
T
Department of Bioinformatics and Computational Biology, George Mason University, Manassas, Virginia 20110, USA.
Klimov
Dmitri K
DK
D000595:Amino Acid Sequence; D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000235:genetics; D001224:Aspartic Acid / Q000737:chemistry; D003198:Computer Simulation; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008954:Models, Biological; D008968:Molecular Conformation; D008969:Molecular Sequence Data; D009154:Mutation; D010455:Peptides / Q000737:chemistry*; D017433:Protein Structure, Secondary; D012997:Solvents / Q000737:chemistry; D013816:Thermodynamics; D014443:Tyrosine / Q000737:chemistry
D016229:Amyloid beta-Peptides; D010455:Peptides; D012997:Solvents; D001224:Aspartic Acid; D014443:Tyrosine