title: Protective V127 prion variant prevents prion disease by interrupting the formation of dimer and fibril from molecular dynamics simulations.
abstract: Recent studies uncovered a novel protective prion protein variant: V127 variant, which was reported intrinsically resistant to prion conversion and propagation. However, the structural basis of its protective effect is still unknown. To uncover the origin of the protective role of V127 variant, molecular dynamics simulations were performed to explore the influence of G127V mutation on two key processes of prion propagation: dimerization and fibril formation. The simulation results indicate V127 variant is unfavorable to form dimer by reducing the main-chain H-bond interactions. The simulations of formed fibrils consisting of β1 strand prove V127 variant will make the formed fibril become unstable and disorder. The weaker interaction energies between layers and reduced H-bonds number for V127 variant reveal this mutation is unfavorable to the formation of stable fibril. Consequently, we find V127 variant is not only unfavorable to the formation of dimer but also unfavorable to the formation of stable core and fibril, which can explain the mechanism on the protective role of V127 variant from the molecular level. Our findings can deepen the understanding of prion disease and may guide the design of peptide mimetics or small molecule to mimic the protective effect of V127 variant.
authors.affiliation: School of Pharmacy, Lanzhou University, Lanzhou 730000, China.|State Key Laboratory of Applied Organic Chemistry and Department of Chemistry, Lanzhou University, Lanzhou 730000, China.
authors.forename: Shuangyan
authors.initials: S
authors.lastname: Zhou
authors.affiliation: State Key Laboratory of Applied Organic Chemistry and Department of Chemistry, Lanzhou University, Lanzhou 730000, China.
authors.forename: Danfeng
authors.initials: D
authors.lastname: Shi
authors.affiliation: State Key Laboratory of Applied Organic Chemistry and Department of Chemistry, Lanzhou University, Lanzhou 730000, China.
authors.forename: Xuewei
authors.initials: X
authors.lastname: Liu
authors.affiliation: School of Pharmacy, Lanzhou University, Lanzhou 730000, 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 730000, 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: D020022:Genetic Predisposition to Disease; D006801:Humans; D006860:Hydrogen Bonding; D056004:Molecular Dynamics Simulation; D020125:Mutation, Missense; D011110:Polymorphism, Genetic; D017096:Prion Diseases / Q000235:genetics*; D000072002:Prion Proteins / Q000737:chemistry / Q000235:genetics*; D065840:Protective Factors; D011485:Protein Binding; D000072756:Protein Conformation, alpha-Helical; D055503:Protein Multimerization; D013816:Thermodynamics
chemical_list: D000072002:Prion Proteins