Computational Design of Novel Inhibitors against Amyloid and#946; Peptide Aggregation

Abstract

The recent studies highlighted that lysine residues (K16 and K28) play a critical role in the newlineAand#946;42 self-assembly and are the target of entities like molecular tweezers (MT). Thus, to newlineunderstand the molecular mechanism behind reduced Aand#946; toxicity on K16A and K28A newlinemutation, explicit solvent MD simulations were performed in water. MD simulations newlinehighlight that modulation of aggregation in K16A and K28A is linked to the increase in the newlineoverall helix content, decrease in the and#946;and#61485;sheet content and enhanced density of water newlinemolecules around the first solvation shell. newlineThe and#946;-sheet breaker (BSB) peptides have several important characteristics, which makes them newlinepotential Aand#946;42 anti-aggregation agents. A simple and effective in silico screening newlinemethodology was reported to evaluate a ~900 peptide library that was designed based on the newlinewell-known BSB peptide, LPFFD. The molecular basis of Aand#946;42 protofibril structural newlinedestabilization by the top hits from the BSB peptide library was highlighted with the newlineconformational microstates analysis, a decrease in the and#946;-sheet propensity of Aand#946;42 protofibril newlineresidues in presence of BSB peptides, a loss of intra-peptide hydrogen bonds, Asp23-Lys28 newlinesalt bridge destabilization and the analysis of free energy surfaces. newlineThe work presented in the thesis provides a detailed atomistic picture of Aand#946; aggregation and newlineits interaction with small molecule and peptide inhibitors. In addition, the mechanistic newlineinsights from the K16A/K28A study will be beneficial for the design and development of newlinenovel inhibitors that will bind and block the interactions, mediated by lysine residues newlinespecifically, critical for the Aand#946;42 self-assembly in AD. The computational design newlinemethodology of the BSB peptides against Aand#946;42 protofibril disassembly provides opportunity newlinefor the design of more potent inhibitors against AD. Overall, the studies listed in the present newlinethesis will provide a pathway to the drug discovery scientists for the future design of more newlinepotent inhibitors against Aand#946;42 aggregation. newline newline