Alanine Scanning Mutagenesis of Aβ(17-42) Amyloid Fibril Stability by Molecular Dynamics Simulations

• Main Authors: Wen-yuan Chu, 朱文淵
• Other Authors: Hui-Hsu Gavin Tsai
• Format: Others
• Language: en_US
• Published: 2015
• Online Access: http://ndltd.ncl.edu.tw/handle/xfnzx5

碩士 === 國立中央大學 === 化學學系 === 103 === Alzheimer’s disease (AD) is characterized by the extracellular deposit of senile plaques in the brain. Senile plaques are mainly composed of the aggregated amyloid beta (Aβ) protein called amyloid. Amyloid fibrils are semi-ordered nanostructures as the result of self-assembly of proteins when they are misfolded under critical conditions. Due to the complexity of Aβ amyloids, the underlying biophysical mechanisms of formation and stability of amyloid fibril are still unclear. Therefore, it is crucial to determine the factors in stabilizing Aβ amyloid fibrils. Motivated by Ala mutagenesis in biochemical research, we employed all-atom molecular dynamics simulations to investigate the relative stability of Aβ-fibril like oligomer and its mutants by alanine mutagenesis. To investigate the intra-peptide interactions, we simulated the structures of Aβ-fibril like oligomer with one of its residue is systemically mutated to Alanine by MD simulations. The secondary structure, salt-bridge between D23 and K28, RMSF and RMSD deviated from the solid-state NMR determined structure are analyzed. Our results show wild type as well as most mutants have their C-terminal residues bent. In general, the strands 2 are less stable and strands 1 are relatively more stable. Gly residues are -sheet breaker. Ala mutagenesis of Gly residues generally enhances the -sheet propensity locally. Swapping the two packed residues on strands1 and 2 does not cause the instability of amyloid fibril indicating that the packing interactions are important in stabilizing amyloid fibril. Our study systemically investigates the roles of side chain of each residue on the stability of amyloid fibrils.