The Role of Electrostatic Interaction in Triggering the Unraveling of Stable Helix 1 in Normal Prion Protein. A Molecular Dynamics Simulation Investigation

Abstract

The conversion of normal prion protein (PrPC) into scrapie isoform (PrPSc) is a key event in the pathogenesis of prion diseases. However, the conversion mechanism has given rise to much controversy. For instance, there is much debate on the behavior of helix 1 (H1) in the conversion. A series of experiments demonstrated that H1 in isolated state was very stable under a variety of conditions. But, other experiments indicated that helices 2 and 3 rather than H1 were retained in PrPSc. In this paper, molecular dynamics (MD) simulation is employed to investigate the dynamic behavior of H1. It is revealed that although the helix 1 of Human PrPC (HuPrPC) is very stable in the isolated state, it becomes unstable when incorporated into native HuPrPC, which likely results from the long-range electrostatic interaction between Asp147 and Arg208 located in the helices 1 and 3, respectively. This explanation is supported by experimental evaluation and MD simulation on D147N mutant of HuPrPC that the mutant becomes a little more stable than the wild type HuPrPC. This finding not only help to reconcile the existing debate on the role of helix 1 in the PrPC-->PrPSc transition, but also reveals a possible mechanism for triggering the PrPC-->PrPSc conversion.

Copper binding sites in the C‐terminal domain of mouse prion protein: A hybrid (QM/MM) molecular dynamics study

“…The role of this helix in the process of misfolding is still controversial; possible roles as a nucleus of the conversion or as a barrier for the same process have been suggested (Ref. 49 and references therein). The putative binding site identified in proximity of H140 involves M138 and D147.…”

“…To shed some light on the controversial topic of copper binding sites and to provide specific data that can help probing putative sites, we performed a theoretical characterization of the structural and chemical properties of the copper loaded C‐terminal domain of the mouse prion protein [PrP(124–226)] 2. Computational studies of PrP have so far been limited to classical MD simulations of the metal‐free C‐terminal domain44–48 or portions of it 44, 49, 50. The binding of open‐shell transition‐metal ions can imply strong polarization, and charge transfer effects and different coordination geometries that are not easily described within standard force fields.…”

The effect of heme on the conformational stability of micro‐myoglobin

“…Structures were saved every 0.5 ps for a total of 3000 snapshots for each trajectory. All of the constant volume constant temperature MD simulations were performed by the Discover module of the insightii program package (Accelys Inc., San Diego, CA), which has been widely employed in MD simulation studies [25][26][27][28]. The consistent valence force field [29][30][31][32] was used for all of the simulations.…”

Dynamics study on the stability of animal prion proteins

“…However, the RMSD of α1 was found to b changed with small amplitude and kept under 3 Å. Previous experimental and theoretical studie have also demonstrated that isolated α1 of mammalian PrPc is very stable [31][32][33]. With th analysis of MD trajectory it was found that α1 was away from the other two helices, which resulte MD process.…”