Enhanced Sampling Molecular Dynamics Identifies PrP^Sc Structures Harboring a C-Terminal β-Core

Abstract

We perform a replica exchange molecular dynamics simulation corresponding to a 2.8 μs total time for the extensive enhanced sampling of the conformational space of the C-terminal part (residues 124-226) of the mouse prion protein (PrP); 1.3% of the conformations sampled display a high level of β-structure (≥19 residues), allowing the assessment of β-propensities along the sequence and highlighting the most structurally labile hot spots. A clustering algorithm is applied to sort the structures of this pool according to their fold. Ten β-rich folds are thus defined and analyzed with regard to their topology, accumulation temperatures, and structural characteristics. In contrast to the so-called spiral and β-helix models suggesting that the β-rich core of the scrapie isoform (PrP(Sc)) comprises the N-terminal tail and part of the C-terminal domain up to helix 1 (H1), we present putative structural models for monomeric precursors of PrP(Sc) and PrP β-oligomers that are characterized by a C-terminal β-rich core, in agreement with the suggestions of a series of recent experiments.

Two Misfolding Routes for the Prion Protein around pH 4.5

“…Many in vitro [5], [8]–[11] and computational [2], [12]–[16] studies have tackled this issue using acidic conditions. They have consistently shown that low pH destabilizes PrP and favors its misfolding.…”

Prion versus Doppel Protein Misfolding: New Insights from Replica-Exchange Molecular Dynamics Simulations

“…39 Here, we briefly review the main aspects of our methodology and highlight the specificities of the simulations we performed for Dpl. We refer the reader to ref 39 for more details.…”

“…59 The simulation length was 56.4 ns for each replica (corresponding to a total time of 1.8 μs). It was chosen on the basis of our previous convergence analysis performed in ref 39 using the fact that, after tens of nanoseconds, we do not seem to sample a significant amount of new conformational clusters. This is illustrated by the time evolution of the fraction of collapsed structures that reaches a plateau at the end of the simulation ( Figure S4 of ref 39).…”

“…The main advantage of this approach is that it allows us to overcome high energy barriers that the system has to cross to convert from one fold (e.g., the native state) to another (e.g., a misfolded state), because of the large temperature interval that the simulation replicas span. 39 Thermal Stability from REMD Simulations. For a more comprehensive picture of the overall conformational landscape of PrP and Dpl, we performed extensive explicit solvent REMD simulations.…”

“…In a previous study [Baillod, P., et al (2012) Biochemistry 51, 9891−9899], we investigated the misfolding and rare, β-rich folds of monomeric PrP with replica-exchange molecular dynamics (REMD) simulations. In the work presented here, we perform analogous simulations for Dpl with the aim of comparing the two systems and characterizing possible specificities of PrP for misfolding and amyloidogenesis.…”