02193nas a2200157   4500008004100000022001400041245014400055210006900199260011000268300001400378490000700392520146300399100001701862700002501879856013101904       2015                        eng d  a1742-206X00aPerturbations in inter-domain associations may trigger the onset of pathogenic transformations in PrPC: insights from atomistic simulations0 aPerturbations in interdomain associations may trigger the onset   aTHOMAS GRAHAM HOUSE, SCIENCE PARK, MILTON RD, CAMBRIDGE CB4 0WF, CAMBS, ENGLANDbROYAL SOC CHEMISTRYcMAR  a1443-14530 v113 a<p>Conversion of the predominantly alpha-helical cellular prion protein (PrPC) to the misfolded beta-sheet enriched Scrapie form (PrPSc) is a critical event in prion pathogenesis. However, the conformational triggers that lead to the isoform conversion (PrPC to PrPSc) remain obscure, and conjectures about the role of unusually hydrophilic, short helix H1 of the C-terminal globular domain in the transition are varied. Helix H1 is anchored to helix H3 via a few stabilizing polar interactions. We have employed fully atomistic molecular dynamics simulations to study the effects triggered by a minor perturbation in the network of these non-bonded interactions in PrPC. The elimination of just one of the key H1-H3 hydrogen bonds led to a cascade of conformational changes that are consistent with those observed in partially unfolded intermediates of PrPC, with pathogenic mutations and in low pH environments. Our analyses reveal that the perturbation results in the enhanced conformational flexibility of the protein. The resultant enhancement in the dynamics leads to overall increased solvent exposure of the hydrophobic core residues and concomitant disruption of the H1-H3 inter-domain salt bridge network. This study lends credence to the hypothesis that perturbing the cooperativity of the stabilizing interactions in the PrPC globular domain can critically affect its dynamics and may lead to structural transitions of pathological relevance.</p>1 aMenon, Sneha1 aSengupta, Neelanjana  uhttps://library.ncl.res.in/content/perturbations-inter-domain-associations-may-trigger-onset-pathogenic-transformations-prpc-0