Computational Studies of the Structural Stability of Rabbit Prion Protein Compared to Human and Mouse Prion Proteins

Prion diseases are invariably fatal and highly infectious neurodegenerative diseases affecting humans and animals. The neurodegenerative diseases such as Creutzfeldt-Jakob disease, variant Creutzfeldt-Jakob diseases, Gerstmann-Str$\ddot{a}$ussler-Scheinker syndrome, Fatal Familial Insomnia, Kuru in humans, scrapie in sheep, bovine spongiform encephalopathy (or 'mad-cow' disease) and chronic wasting disease in cattle belong to prion diseases. By now there have not been some effective therapeutic approaches to treat all these prion diseases. Dogs, rabbits and horses were reported to be resistant to prion diseases. By the end of year 2010 all the NMR structures of dog, rabbit and horse prion proteins (X-ray for rabbits too) had been finished to release into protein data bank. Thus, at this moment it is very worth studying the NMR and X-ray molecular structures of horse, dog and rabbit prion proteins to obtain insights into their immunity prion diseases. The author found that dog and horse prion proteins have stable molecular dynamical structures whether under neutral or low pH environments, but rabbit prion protein has stable molecular dynamical structures only under neutral pH environment. Under low pH environment, the stable $\alpha$-helical molecular structures of rabbit prion protein collapse into $\beta$-sheet structures. This article focuses the studies on rabbit prion protein (within its C-terminal NMR, Homology and X-ray molecular structured region RaPrP$^\text{C}$ (120-230)), compared with human and mouse prion proteins (HuPrP$^\text{C}$ (125-228) and MoPrP$^\text{C}$ (124-226) respectively). The author finds that some salt bridges contribute to the structural stability of rabbit prion protein under neutral pH environment.Comment: Contributed as an invited Book Chapter to "Neurodegenerative Diseases / Book 2, Raymond Chuen-Chung Chang (eds.), INTECH Open Access Publisher, 2011, ISBN 979-953-307-672-9

The polar clasps of a bank vole PrP(168--176) prion protofibril revisiting

On 2018-01-17 two electron crystallography structures (with PDB entries 6AXZ, 6BTK) on a prion protofibril of bank vole PrP(168-176) (a segment in the PrP $\beta$2-$\alpha$2 loop) were released into the PDB Bank. The paper published by [Nat Struct Mol Biol 25(2):131-134 (2018)] reports some polar clasps for these two crystal structures, and "an intersheet hydrogen bond between Tyr169 and the backbone carbonyl of Asn171 on an opposing strand." - this hydrogen bond is not between the neighbouring Chain B and Chain A directly. In addition, by revisiting the polar clasps, we found another two hydrogen bonds ([email protected]@OE1, [email protected]@N) between the strand A of one sheet and the opposing strand B of the mating sheet. For the neighbouring two single $\beta$-sheets AB, the two new hydrogen bonds are completely different from the experimental one (an intersheet hydrogen bond between Tyr169 and the backbone carbonyl of Asn171 on an opposing strand) in [Nat Struct Mol Biol 25(2):131-134 (2018)]

Molecular Dynamics Studies on 3D Structures of the Hydrophobic Region PrP(109-136)

Prion diseases caused by the conversion from a soluble normal cellular prion protein into insoluble abnormally folded infectious prions, are invariably fatal and highly infectious degenerative diseases that affect a wide variety of mammalian species. The palindrome and the Glycine-rich conserved segment in the hydrophobic region 109-136 control the conversion from normal prion protein to form into diseased prions. This paper gives detailed reviews on the 109-136 region and presents the studies of its 3D structures and structural dynamics.Comment: This paper was accepted on 18-02-2013 by the journal Acta Biochimica et Biophysica Sinica, in press in Vol 45 No 4, Apr 201

A Review on the Salt Bridge Between ASP177 and ARG163 of Wild-Type Rabbit Prion Protein

Prion diseases are invariably fatal and highly infectious neurodegenerative diseases that affect a wide variety of mammalian species such as sheep and goats, cattle, deer, elks, humans and mice etc., but rabbits have a low susceptibility to be infected by prion diseases with respect to other species. The stability of rabbit prion protein is due to its highly ordered {\beta}2-{\alpha}2 loop (PLoS One 5(10) e13273 (2010); Journal of Biological Chemistry 285(41) 31682-31693 (2010)) and a hydrophobic staple helix-capping motif (PNAS 107(46) 19808-19813 (2010); PLoS One 8 (5) e63047 (2013)). The {\beta}2-{\alpha}2 loop and the tail of Helix 3 it interacts with have been a focus in prion protein structure studies. For this loop we found a salt bridge linkage ASP177-ARG163 (O-N) (Journal of Theoretical Biology 342 (7 February 2014) 70-82 (2014)). Some scientists said on the 2FJ3.pdb NMR file of the rabbit prion protein, the distance of ASP177-ARG163 (O-N) gives the salt bridge of about 10 {\AA} which is nearly null in terms of energy and such a salt bridge is not observed in their work. But, from the 3O79.pdb X-ray file of the rabbit prion protein, we can clearly observe this salt bridge. This article analyses the NMR and X-ray structures and gives an answer to the above question: the salt bridge presents at pH 6.5 in the X-ray structure is simply gone at pH 4.5 in the NMR structure is simply due to the different pH values that impact electrostatics at the salt bridge and hence also impact the structures. Moreover, some molecular dynamics simulation results of the X-ray structure are reported in this article to reveal the secrets of the structural stability of rabbit prion protein.Comment: arXiv admin note: text overlap with arXiv:1407.622