title: Structural diversity and initial oligomerization of PrP106-126 studied by replica-exchange and conventional molecular dynamics simulations.
abstract: Prion diseases are marked by cerebral accumulation of the abnormal isoform of the prion protein. A fragment of prion protein composed of residues 106-126 (PrP106-126) exhibits similar properties to full length prion and plays a key role in the conformational conversion from cellular prion to its pathogenic pattern. Soluble oligomers of PrP106-126 have been proposed to be responsible for neurotoxicity. However, the monomeric conformational space and initial oligomerization of PrP106-126 are still obscure, which are very important for understanding the conformational conversion of PrP106-126. In this study, replica exchange molecular dynamics simulations were performed to investigate monomeric and dimeric states of PrP106-126 in implicit solvent. The structural diversity of PrP106-126 was observed and this peptide did not acquire stable structure. The dimeric PrP106-126 also displayed structural diversity and hydrophobic interaction drove the dimerization. To further study initial oligomerization of PrP106-126, 1 µs conventional molecular dynamics simulations of trimer and tetramer formation were carried out in implicit solvent. We have observed the spontaneous formation of several basic oligomers and stable oligomers with high β-sheet contents were sampled in the simulations of trimer and tetramer formation. The β-hairpin formed in hydrophobic tail of PrP106-126 with residues 118-120 in turn may stabilize these oligomers and seed the formation oligomers. This study can provide insight into the detailed information about the structure of PrP106-126 and the dynamics of aggregation of monomeric PrP106-126 into oligomers in atomic level.
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 Pharmacy, Lanzhou University, Lanzhou, China.
authors.forename: Jingjing
authors.initials: J
authors.lastname: Guo
authors.affiliation: State Key Laboratory of Applied Organic Chemistry and Department of Chemistry, Lanzhou University, Lanzhou, China.
authors.forename: Qifeng
authors.initials: Q
authors.lastname: Bai
authors.affiliation: Gansu Computing Center, Lanzhou, China.
authors.forename: Nengzhi
authors.initials: N
authors.lastname: Jin
authors.affiliation: State Key Laboratory of Applied Organic Chemistry and Department of Chemistry, Lanzhou University, Lanzhou, China ; 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 Lab for Quality Research in Chinese Medicines, 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; D006801:Humans; D056004:Molecular Dynamics Simulation; D010446:Peptide Fragments / Q000737:chemistry*; D011328:Prions / Q000737:chemistry*; D055503:Protein Multimerization; D017433:Protein Structure, Secondary
chemical_list: D010446:Peptide Fragments; D011328:Prions; C082632:prion protein (106-126)