Molecular dynamics studies on the NMR and X-ray structures of rabbit prion proteins

• Published in: Journal of theoretical biology Vol. 342; pp. 70 - 82
• Main Authors: Zhang, Jiapu, Zhang, Yuanli
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 07.02.2014
• Subjects: Animals; Hydrogen Bonding; Hydrogen-Ion Concentration; Magnetic Resonance Spectroscopy; Molecular Dynamics Simulation; Molecular dynamics study; NMR and X-ray structures; Prion diseases; Prions - chemistry; Protein Structure, Secondary; Rabbit prion proteins; Rabbits; Temperature; Wild-type and mutants; X-Rays; Prion diseases; Molecular dynamics study; Wild-type and mutants; Rabbit prion proteins; NMR and X-ray structures
• ISSN: 0022-5193; 1095-8541
• DOI: 10.1016/j.jtbi.2013.10.005

Prion diseases, traditionally referred to as transmissible spongiform encephalopathies (TSEs), are invariably fatal and highly infectious neurodegenerative diseases that affect a wide variety of mammalian species, manifesting as scrapie in sheep and goats, bovine spongiform encephalopathy (BSE or mad-cow disease) in cattle, chronic wasting disease in deer and elk, and Creutzfeldt–Jakob diseases, Gerstmann–Sträussler–Scheinker syndrome, fatal familial insomnia, and kulu in humans, etc. These neurodegenerative diseases are caused by the conversion from a soluble normal cellular prion protein (PrPC) into insoluble abnormally folded infectious prions (PrPSc), and the conversion of PrPC to PrPSc is believed to involve conformational change from a predominantly α-helical protein to one rich in β-sheet structure. Such a conformational change may be amenable to study by molecular dynamics (MD) techniques. For rabbits, classical studies show that they have a low susceptibility to be infected by PrPSc, but recently it was reported that rabbit prions can be generated through saPMCA (serial automated Protein Misfolding Cyclic Amplification) in vitro and the rabbit prion is infectious and transmissible. In this paper, we first do a detailed survey on the research advances of rabbit prion protein (RaPrP) and then we perform MD simulations on the NMR and X-ray molecular structures of rabbit prion protein wild-type and mutants. The survey shows to us that rabbits were not challenged directly in vivo with other known prion strains and the saPMCA result did not pass the test of the known BSE strain of cattle. Thus, we might still look rabbits as a prion resistant species. MD results indicate that the three α-helices of the wild-type are stable under the neutral pH environment (but under low pH environment the three α-helices have been unfolded into β-sheets), and the three α-helices of the mutants (I214V and S173N) are unfolded into rich β-sheet structures under the same pH environment. In addition, we found an interesting result that the salt bridges such as ASP201–ARG155, ASP177–ARG163 contribute greatly to the structural stability of RaPrP. •Classical studies show that rabbits have a low susceptibility to be infected by the infectious prions of prion diseases.•Recently rabbit prions were generated through saPMCA in vitro, and the rabbit prion is infectious and transmissible.•This paper did a survey on research advances of rabbit PrP.•This paper also did molecular dynamics studies of NMR and X-ray structures of all rabbit prion proteins.