02621nas a2200157   4500008004100000022001400041245012800055210006900183260007100252300001400323490000800337520194500345100002702290700002302317856012302340       2016                        eng d  a1520-610600aReplica exchange molecular dynamics study of dimerization in prion protein: multiple modes of interaction and stabilization0 aReplica exchange molecular dynamics study of dimerization in pri  a1155 16TH ST, NW, WASHINGTON, DC 20036 USAbAMER CHEMICAL SOCcAUG  a7332-73450 v1203 a<p>The pathological forms of prions are known to be a result of misfolding, oligomerization, and aggregation of the cellular prion. While the mechanism of misfolding and aggregation in prions has been widely studied using both experimental and computational tools, the structural and energetic characterization of the dimer form have not garnered as much attention. On one hand dimerization can be the first step toward a nucleation-like pathway to aggregation, whereas on the other hand it may also increase the conformational stability preventing self-aggregation. In this work, we have used extensive all-atom replica exchange molecular dynamics simulations of both monomer and dimer forms of a mouse prion protein to understand the structural, dynamic, and thermodynamic stability of dimeric prion as compared to the monomeric form. We show that prion proteins can dimerize spontaneously being stabilized by hydrophobic interactions as well as intermolecular hydrogen bonding and salt bridge formation. We have computed the conformational free energy landscapes for both monomer and dimer forms to compare the thermodynamic stability and misfolding pathways. We observe large conformational heterogeneity among the various modes of interactions between the monomers and the strong intermolecular interactions may lead to as high as 20% beta-content. The hydrophobic regions in helix-2, surrounding coil regions, terminal regions along with the natively present beta-sheet region appear to actively participate in prion-prion intermolecular interactions. Dimerization seems to considerably suppress the inherent dynamic instability observed in monomeric prions, particularly because the regions of structural frustration constitute the dimer interface. Further, we demonstrate an interesting reversible coupling between the Q160-G131 interaction (which leads to inhibition of beta-sheet extension) and the G131-V161 H-bond formation.</p>1 aChamachi, Neharika, G.1 aChakrabarty, Suman  uhttps://library.ncl.res.in/content/replica-exchange-molecular-dynamics-study-dimerization-prion-protein-multiple-modes02362nas a2200157   4500008004100000022001400041245014200055210006900197260000900266300001200275490000700287520173000294100002702024700002302051856013002074       2017                        eng d  a0006-296000aTemperature-induced misfolding in prion protein: evidence of multiple partially disordered states stabilized by non-native hydrogen bonds0 aTemperatureinduced misfolding in prion protein evidence of multi  cFEB   a833-8440 v563 a<p>The structural basis of pathways of misfolding of a cellular prion (PrPc) into the toxic scrapie form (PrPsc) and identification of possible intermediates (e.g., PrP*) still eludes us. In this work, we have used a cumulative us of replica exchange molecular dynamics simulation data to construct the conformational free energy landscapes and capture the structural and thermodynamic characteristics associated with various stages of the thermal denaturation process in human prion protein. The temperature-dependent free energy surfaces consist of multiple metastable states stabilized by non-native contacts and hydrogen bonds, thus rendering the protein prone to misfolding. We have been able to identify metastable conformational states with high beta-content (similar to 30-40%) and low alpha-content (similar to 10-20%) that might be precursors of PrPsc oligomer formation. These conformations also involve participation of the unstructured N-terminal domain, and its role in misfolding has been investigated. All the misfolded or partially unfolded states are quite compact in nature despite having large deviations from the native structure. Although the number of native contacts decreases dramatically at higher temperatures, the radius of gyration and number of intraprotein hydrogen bonds and contacts remain relatively unchanged, leading to stabilization of the misfolded conformations by non-native interactions. Our results are in good agreement with the established view that the C-terminal regions of the second and third helices (H2 and H3, respectively) of mammal prions might be the Achilles heels of their stability, while separation of B1-H1-B2 and H2-H3 domains seems to play a key role, as well.</p>1 aChamachi, Neharika, G.1 aChakrabarty, Suman  uhttps://library.ncl.res.in/content/temperature-induced-misfolding-prion-protein-evidence-multiple-partially-disordered-states