title: 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.
authors.affiliation: State Key Laboratory of Applied Organic Chemistry and Department of Chemistry, Lanzhou University, Lanzhou, China.
authors.forename: Lulu
authors.initials: L
authors.lastname: Ning
authors.affiliation: State Key Laboratory of Applied Organic Chemistry and Department of Chemistry, Lanzhou University, Lanzhou, China; School of pharmaceutical technology, Qiandongnan National Polytechnic, Kaili, China.
authors.forename: Dabo
authors.initials: D
authors.lastname: Pan
authors.affiliation: School of Pharmacy, Lanzhou University, Lanzhou, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Applied Organic Chemistry and Department of Chemistry, Lanzhou University, Lanzhou, China.
authors.forename: Shaopeng
authors.initials: S
authors.lastname: Wang
authors.affiliation: School of Pharmacy, Lanzhou University, Lanzhou, China.
authors.forename: Huanxiang
authors.initials: H
authors.lastname: Liu
authors.affiliation: State Key Laboratory of Applied Organic Chemistry and Department of Chemistry, Lanzhou University, Lanzhou, China; State Key Laboratory of Quality Research in Chinese Medicine, Macau Institute for Applied Research in Medicine and Health, Macau University of Science and Technology, Taipa, Macau, China.
authors.forename: Xiaojun
authors.initials: X
authors.lastname: Yao
mesh_terms: D000595:Amino Acid Sequence; D057927:Hydrophobic and Hydrophilic Interactions; D056004:Molecular Dynamics Simulation; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D010446:Peptide Fragments / Q000235:genetics / Q000378:metabolism*; D011328:Prions / Q000235:genetics* / Q000378:metabolism*; D066329:Protein Aggregates / Q000235:genetics*; D017510:Protein Folding; D017433:Protein Structure, Secondary
chemical_list: D010446:Peptide Fragments; D011328:Prions; D066329:Protein Aggregates