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Molecular dynamics simulation of dimeric and monomeric forms of human prion protein: insight into dynamics and properties.

ABSTRACT: A central theme in prion protein research is the detection of the process that underlies the conformational transition from the normal cellular prion form (PrP(C)) to its pathogenic isoform (PrP(Sc)). Although the three-dimensional structures of monomeric and dimeric human prion protein (HuPrP) have been revealed by NMR spectroscopy and x-ray crystallography, the process underlying the conformational change from PrP(C) to PrP(Sc) and the dynamics and functions of PrP(C) remain unknown. The dimeric form is thought to play an important role in the conformational transition. In this study, we performed molecular dynamics (MD) simulations on monomeric and dimeric HuPrP at 300 K and 500 K for 10 ns to investigate the differences in the properties of the monomer and the dimer from the perspective of dynamic and structural behaviors. Simulations were also undertaken with Asp178Asn and acidic pH, which is known as a disease-associated factor. Our results indicate that the dynamics of the dimer and monomer were similar (e.g., denaturation of helices and elongation of the beta-sheet). However, additional secondary structure elements formed in the dimer might result in showing the differences in dynamics and properties between the monomer and dimer (e.g., the greater retention of dimeric than monomeric tertiary structure).

SUBMITTER: Sekijima M

PROVIDER: S-EPMC1303235 | biostudies-literature | 2003 Aug

REPOSITORIES: biostudies-literature

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Molecular dynamics simulation of dimeric and monomeric forms of human prion protein: insight into dynamics and properties.

Sekijima Masakazu M Motono Chie C Yamasaki Satoshi S Kaneko Kiyotoshi K Akiyama Yutaka Y

Biophysical journal 20030801 2

A central theme in prion protein research is the detection of the process that underlies the conformational transition from the normal cellular prion form (PrP(C)) to its pathogenic isoform (PrP(Sc)). Although the three-dimensional structures of monomeric and dimeric human prion protein (HuPrP) have been revealed by NMR spectroscopy and x-ray crystallography, the process underlying the conformational change from PrP(C) to PrP(Sc) and the dynamics and functions of PrP(C) remain unknown. The dimer ...[more]

PMID: 12885661

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Project description:Technical strategies like amino acid substitution and residue modification have been widely used to characterize the importance of key amino acids and the role that each residue plays in the structural and functional properties of protein molecules. However, there is no systematic approach to assess the impact of the substituted/modified amino acids on the conformational dynamics of proteins. In this investigation to clarify the effects of residue modifications on the structural dynamics of human prion protein (PrP), a comparative molecular dynamics simulation study on the native and the amino acid-substituted analog at position 208 of PrP has been performed. It is believed that Arginine to Histidine mutation at position 208 is responsible for the structural transition of the native form of human prion protein to the pathogenic isoform causing Creutzfeldt-Jakob disease (CJD). So, three 10 ns molecular dynamics simulations on three model constructs have been performed. Simulation results indicated considerable differences of conformational fluctuations for Alanine substituted construct (PrPALA) and the analog form (PrPSB) comprising the neutralized state of the Arginine residue at position 208 of the human prion protein. According to our data, substitution of the Arginine residue by the uncharged state of this residue induces some reversible structural alterations in the intrinsically flexible loop area including residues 167-171 of PrP. Thus, deprotonation of Arg(208) is a weak perturbation to the structural fluctuations of the protein backbone and the resulting construct behaves almost identical as its native form. Otherwise, Alanine substitution at position 208 imposed an irreversible impact on the secondary and tertiary structure of the protein, which leads to conformational instabilities in the remote hot region comprising residues 190-195 of the C-terminal part of helix 2. Based on the results, it could be deduced that the observed conformational transitions upon Arg(208) to His point mutation, which is the main reason for CJD, may be mainly related to the structural instabilities due to the induced-conformational changes that caused alterations in local/spatial arrangements of the force distributions in the backbone of the human prion protein.

Dataset Information

Molecular dynamics simulation of dimeric and monomeric forms of human prion protein: insight into dynamics and properties.

Publications

Molecular dynamics simulation of dimeric and monomeric forms of human prion protein: insight into dynamics and properties.

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