title: Temperature-Induced Misfolding in Prion Protein: Evidence of Multiple Partially Disordered States Stabilized by Non-Native Hydrogen Bonds.
abstract: 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 ∼65 μs 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 β-content (∼30-40%) and low α-content (∼10-20%) that might be precursors of PrPSColigomer 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.
authors.affiliation: Physical and Materials Chemistry Division, CSIR-National Chemical Laboratory , Pune 411008, India.
authors.forename: Neharika G
authors.initials: NG
authors.lastname: Chamachi
authors.affiliation: Physical and Materials Chemistry Division, CSIR-National Chemical Laboratory , Pune 411008, India.
authors.forename: Suman
authors.identifier: 0000-0002-9461-0015
authors.initials: S
authors.lastname: Chakrabarty
mesh_terms: D030562:Databases, Protein; D004735:Energy Transfer; D006358:Hot Temperature / Q000009:adverse effects; D006801:Humans; D006860:Hydrogen Bonding; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D019906:Nuclear Magnetic Resonance, Biomolecular; D010446:Peptide Fragments / Q000737:chemistry* / Q000378:metabolism; D018621:PrPC Proteins / Q000737:chemistry* / Q000378:metabolism; D000072002:Prion Proteins / Q000737:chemistry* / Q000378:metabolism; D066263:Protein Aggregation, Pathological / Q000378:metabolism / Q000473:pathology; D011487:Protein Conformation; D011489:Protein Denaturation; D017510:Protein Folding; D054730:Protein Interaction Domains and Motifs; D055550:Protein Stability; D013499:Surface Properties
chemical_list: D010446:Peptide Fragments; D018621:PrPC Proteins; D000072002:Prion Proteins; C000618857:prion protein (124-231); C000618858:prion protein (90-123)