Reversibility of Prion Misfolding: Insights from Constant-pH Molecular Dynamics Simulations

Abstract

The prion protein (PrP) is the cause of a group of diseases known as transmissible spongiform encephalopathies (TSEs). Creutzfeldt-Jakob disease and bovine spongiform encephalopathy are examples of TSEs. Although the normal form of PrP (PrP(C)) is monomeric and soluble, it can misfold into a pathogenic form (PrP(Sc)) that has a high content of β-structure and can aggregate forming amyloid fibrils. The mechanism of conversion of PrP(C) into PrP(Sc) is not known but different triggers have been proposed. It can be catalyzed by a PrP(Sc) sample, or it can be induced by an external factor, such as low pH. The pH effect on the structure of PrP was recently studied by computational methods [Campos et al. J. Phys. Chem. B 2010, 114, 12692-12700], and an evident trend of loss of helical structure was observed with pH decrease, together with a gain of β-structures. In particular, one simulation at pH 2 showed an evident misfolding transition. The main goal of the present work was to study the effects of a change in pH to 7 in several transient conformations of this simulation, in order to draw some conclusions about the reversibility of PrP misfolding. Although the most significant effect caused by the change of pH to 7 was a global stabilization of the protein structure, we could also observe that some conformational transitions induced by pH 2 were reversible in many of our simulations, namely those started from the early moments of the misfolding transition. This observation is in good agreement with experiments showing that, even at pH as low as 1.7, it is possible to revert the misfolding process [Bjorndahl et al. Biochemistry 2011, 50, 1162-1173].

Recent development and application of constant pH molecular dynamics

“…Using the PB-based DpHMD method [12], the Baptista and Machuqueiro groups investigated the pH-dependent conformational change of the prion protein [45, 46] as well as small peptides [47]. Using the GB-based DpHMD method [14], the Roitberg group studied the pH-dependent conformational variability of the Nitrophorin proteins [48, 49].…”

Development of constant-pH simulation methods in implicit solvent and applications in biomolecular systems

“…The results obtained for their studies in a diversity of biomolecular systems reveal the vast possibilities of the method. Examples include investigation on the pH-dependent conformational states of the analgesic dipeptide kyotorphin (L-Tyr-L-Arg) (Machuqueiro and Baptista 2007), the possibility of a trigged pH action on the misfolding of the prion protein into a pathogenic β-rich form (Campos et al 2010), the pH effects on the reversibility of prion misfolding (Vila-Viçosa et al 2012), a pH titration of all constituent lipids of a 25% DMPA/DMPC bilayer membrane model (Santos et al 2015), and the tight coupling between protonation and conformation for cytochrome c oxidase (Oliveira et al 2016).…”

Molecular dynamics simulations of amyloid fibrils: an <italic>in silico</italic> approach

“…It is well known that transition from PrP C to PrP Sc can be induced by infectious PrP Sc , or an external factor, such as low pH [1,2,34]. Many MD simulations have demonstrated the role of pH.…”

“…They found that glycosylation could indeed stabilize the prion protein, indirectly through reducing the mobility of the surrounding solvents. Recently, several research teams have observed that the low pH-induced PrP transition could possibly be reversible, both in experiments and MD simulations [34,40,41]. Even in the strongly acidic environment of pH ¼ 1.7, the misfolding process could be reversed.…”