Roles of Tryptophan and Charged Residues on the Polymorphisms of Amyloids Formed by K-Peptides of Hen Egg White Lysozyme Investigated through Molecular Dynamics Simulations.

Atomistic molecular dynamics simulations of amyloid models, consisting of the previously reported STDY-K-peptides and K-peptides from the hen egg white lysozyme (HEWL), were performed to address the effects of charged residues and pH observed in an in vitro study. Simulation results showed that amyloid models with antiparallel configurations possessed greater stability and compactness than those with parallel configurations. Then, peptide chain stretching and ordering were measured through the end-to-end distance and the order parameter, for which the amyloid models consisting of K-peptides and the STDY-K-peptides at pH 2 displayed a higher level of chain stretching and ordering. After that, the molecular mechanics energy decomposition and the radial distribution function (RDF) clearly displayed the importance of Trp62 to the K-peptide and the STDY-K-peptide models at pH 2. Moreover, the results also displayed how the negatively charged Asp52 disrupted the interaction networks and prevented the amyloid formation from STDY-K-peptide at pH 7. Finally, this study provided an insight into the interplay between pH conditions and molecular interactions underlying the formation of amyloid fibrils from short peptides contained within the HEWL. This served as a basis of understanding towards the design of other amyloids for biomaterial applications.

Molecular dynamics study on the effects of charged amino acid distribution under low pH condition to the unfolding of hen egg white lysozyme and formation of beta strands.

Aggregation of unfolded or misfolded proteins into amyloid fibrils can cause various diseases in humans. However, the fibrils synthesized in vitro can be developed toward useful biomaterials under some physicochemical conditions. In this study, atomistic molecular dynamics simulations were performed to address the mechanism of beta-sheet formation of the unfolded hen egg-white lysozyme (HEWL) under a high temperature and low pH. Simulations of the protonated HEWL at pH 2 and the non-protonated HEWL at pH 7 were performed at the highly elevated temperature of 450 K to accelerate the unfolding, followed by the 333 K temperature to emulate some previous in vitro studies. The simulations showed that HEWL unfolded faster, and higher beta-strand contents were observed at pH 2. In addition, one of the simulation replicas at pH 2 showed that the beta-strand forming sequence was consistent with the 'K-peptide', proposed as the core region for amyloidosis in previous experimental studies. Beta-strand formation mechanisms at the earlier stage of amyloidosis were explained in terms of the radial distribution of the amino acids. The separation between groups of positively charged sidechains from the hydrophobic core corresponded to the clustering of the hydrophobic residues and beta-strand formation.