Effects of the Pathogenic Mutation A117V and the Protective Mutation H111S on the Folding and Aggregation of PrP106-126: Insights from Replica Exchange Molecular Dynamics Simulations

Abstract

The fragment 106-126 of prion protein exhibits similar properties to full-length prion. Experiments have shown that the A117V mutation enhances the aggregation of PrP106-126, while the H111S mutation abolishes the assembly. However, the mechanism of the change in the aggregation behavior of PrP106-126 upon the two mutations is not fully understood. In this study, replica exchange molecular dynamics simulations were performed to investigate the conformational ensemble of the WT PrP106-126 and its two mutants A117V and H111S. The obtained results indicate that the three species are all intrinsically disordered but they have distinct morphological differences. The A117V mutant has a higher propensity to form β-hairpin structures than the WT, while the H111S mutant has a higher population of helical structures. Furthermore, the A117V mutation increases the hydrophobic solvent accessible surface areas of PrP106-126 and the H111S mutation reduces the exposure of hydrophobic residues. It can be concluded that the difference in populations of β-hairpin structures and the change of hydrophobic solvent accessible areas may induce the different aggregation behaviors of the A117V and the H111S mutated PrP106-126. Understanding why the two mutations have contrary effects on the aggregation of PrP106-126 is very meaningful for further elucidation of the mechanism underlying aggregation and design of inhibitor against aggregation process.

Intrinsic Origin of Tau Protein Aggregation: Effects of Histidine Tautomerism on Tau267–312 Monomer

“…To conduct REMD simulations, the AMBER ff99SB nonpolarizable force field and implicit solvent generalized Born model were utilized in the Amber14 biomolecular simulation program. , The AMBER ff99SB empirical force field has been routinely utilized to simulate the aggregation-prone peptide misfolding, which precisely reparametrizes the protein backbone torsion terms in ff99 and accomplishes a much better balance of four fundamental secondary structures. It has shown good correlation with experimental results. − The SHAKE algorithm was used to constrain all the bonds involving H atoms. PME was applied to calculate the long-range electrostatics.…”

Tautomeric Effect of Histidine on the Monomeric Structure of Amyloid β-Peptide(1–40)

“…The ff99SB nonpolarization force field and the implicit solvent generalized Born model were employed to perform the REMD simulations with the Amber 12/Amber14 package . The AMBER ff99SB force field has been frequently used to simulate protein misfolding, − which presents a careful reparametrization of the backbone torsion terms in ff99 and achieves a much better balance of four basic secondary structure elements . The SHAKE algorithm was applied to constrain the bonds including hydrogen.…”

Unraveling the Histidine Tautomerism Effect on the Initial Stages of Prion Misfolding: New Insights from a Computational Perspective

“…There are a number of recent studies that evaluate the applicability of the GB implicit solvent REMD simulation in generating accurate information about the protein conformational dynamics in peptide folding, which also reveal that there is a perfect balance between accuracy and speed . Several groups have already performed implicit solvent-based REMD simulations on distinct PrP monomers to analyze its misfolding and aggregation mechanisms. − Furthermore, AMBER ff99SB, which has been employed to analyze the folding pathway of aggregation-prone peptides, achieves an enhanced balance of crucial secondary structures, like α-helices and sheets . A web server () was utilized to assign the temperature distributions of replicas.…”