Structural and dynamical mechanisms of a naturally occurring variant of the human prion protein in preventing prion conversion*

Abstract

Prion diseases are associated with the misfolding of the normal helical cellular form of prion protein (PrPC) into the β-sheet-rich scrapie form (PrPSc) and the subsequent aggregation of PrPSc into amyloid fibrils. Recent studies demonstrated that a naturally occurring variant V127 of human PrPC is intrinsically resistant to prion conversion and aggregation, and can completely prevent prion diseases. However, the underlying molecular mechanism remains elusive. Herein we perform multiple microsecond molecular dynamics simulations on both wildtype (WT) and V127 variant of human PrPC to understand at atomic level the protective effect of V127 variant. Our simulations show that G127V mutation not only increases the rigidity of the S2–H2 loop between strand-2 (S2) and helix-2 (H2), but also allosterically enhances the stability of the H2 C-terminal region. Interestingly, previous studies reported that animals with rigid S2–H2 loop usually do not develop prion diseases, and the increase in H2 C-terminal stability can prevent misfolding and oligomerization of prion protein. The allosteric paths from G/V127 to H2 C-terminal region are identified using dynamical network analyses. Moreover, community network analyses illustrate that G127V mutation enhances the global correlations and intra-molecular interactions of PrP, thus stabilizing the overall PrPC structure and inhibiting its conversion into PrPSc. This study provides mechanistic understanding of human V127 variant in preventing prion conversion which may be helpful for the rational design of potent anti-prion compounds.

Mechanistic insight into the destabilization of p53TD tetramer by cancer-related R337H mutation: a molecular dynamics study

“…The community network method is a useful strategy for illustrating the connectivity of amino acid residues in biomolecules. 85–90 We constructed the dynamical networks of WT-p53Tet and R337H–p53Tet, and calculated the optimal community distributions using the Girvan–Newman algorithm. 82 Representative community network diagrams of the two tetramers are shown in Fig.…”

Effects of the Pathological E200K Mutation on Human Prion Protein: A Computational screening and Molecular Dynamic approach

“…indicate that the end of B-sheet 1, Helix 2, Helix 3, and the turning region between Helix 2 and Helix 3 can be proposed as a site for initiating protein alterations to β-sheet and aggregation to amyloids. According to the study on prion protein resistance by G127V mutation against prion diseases (28,57) and the results obtained from the MD simulation outputs, it can be interpreted that The G127V mutation prevents structural changes and uctuations in the suggested amyloid initiation region and makes these regions more stable against uctuations and structural rearrangement (12,(58)(59)(60)(61). We have analyzed one of the most deleterious Prion protein nsSNP (E200K) with a various number of bioinformatics servers and also compared our result with some experimentally reported phenotypic effects of the E200K nsSNPs.…”

Effects of the pathological E200K mutation on human prion protein: A computational screening and molecular dynamics approach

“…According to the study on prion protein resistance by G127V mutation against prion diseases 20,58 and the results obtained from the MD simulation outputs, it can be interpreted that The G127V mutation prevents structural changes and fluctuations in the suggested amyloid initiation region and makes these regions more stable against fluctuations and structural rearrangement. 12,[59][60][61][62] We have analyzed one of the most deleterious prion protein nsSNP (E200K) with various bioinformatics servers and also compared our result with some experimentally reported phenotypic effects of the E200K nsSNPs. On the other hand, we have performed a molecular dynamics simulation of the E200K structure, G127V structure, and native protein structure.…”