Insights in the structural understanding of amyloidogenicity and mutation-led conformational dynamics of amyloid beta (Aβ) through molecular dynamics simulations and principal component analysis.

Abnormal protein aggregation in the nervous tissue leads to several neurodegenerative disorders like Alzheimer's disease (AD). In AD, accumulation of the amyloid beta (Aβ) peptide is proposed to be an early important event in pathogenesis. Significant research efforts are devoted so as to understand the Aβ misfolding and aggregation. Molecular dynamics (MD) simulations complement experiments and provide structural information at the atomic level with dynamics without facing the same experimental limitations. Artificial missense mutations are employed experimentally and computationally for providing insights into the structure-function relationships of amyloid-β in relation to the pathologies of AD. Present work describes the MD simulations for 100 ns so as to probe the structural and conformational dynamics of Aβ1-42 assemblies and its mutants. Essential dynamics analysis with respect to conformational deviation of Cα was evaluated to identify the largest residual fluctuation of Cα. Conformational stability of all Aβ mutants was analyzed by computing RMSD, deciphering the convergence is reached in the last 20 ns in all replicas. To highlight the low frequency mode of motion corresponding to the highest amplitude, atomic displacements seen in trajectory, distance pair principal component analysis (dpPCA) was performed, which adumbrated mutations strongly affect the conformational dynamics of investigated model when compared with wild type. Dynamic cross correlation matrix (DCCM) also suggests the conserved interactions of wild Aβ and imply mutations in β3-β4 loop region induce deformity and residual fluctuations as observed from simulation. Present study indicate the mutational energy landscape which induces deformation leading to fibrillation.Communicated by Ramaswamy H. Sarma.