  Prion diseases are associated with the misfolding of the normal helical
cellular form of prion protein (PrPC) into the beta-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.
