Reversibility of prion misfolding by constant-pH molecular dynamics simulations

• Author(s): Viçosa, Diogo Ruivo dos Santos Vila
• Date: 2010
• Persistent ID: http://hdl.handle.net/10451/5451
• Origin: Repositório da Universidade de Lisboa
• Subject(s): Prion protein; pH; Constant-pH molecular dynamics; N-O contacts; Principal component analysis; Misfolding; Teses de mestrado - 2010
• Document Type: Master Thesis
• Language: English
• Advisor(s): Baptista, António M.; Machuqueiro, Miguel Ângelo dos Santos

Description

Tese de mestrado, Bioquímica, Universidade de Lisboa, Faculdade de Ciências, 2010 The prion protein (PrP) is the cause of a group of diseases known as Transmissible Spongiform Encephalopathies (TSEs). Creutzfeldt-Jakob and Bovine Spongiform Encephalopathy are examples of TSEs. The normal form of PrP (PrPC) is monomeric and soluble, however, it can misfold into a pathogenic form (PrPSc). This last form has a high content of β-structures and can aggregate forming amyloid fibrils. The mechanism of conversion between PrPC and PrPSc is not completely elucidated but it can be catalyzed by a PrPSc sample (protein-only hypothesis) or it can be induced by an external factor. The pH seems to be a factor that can induce the misfolding transition and it may occur in the endocytic pathway. The pH effect in the structure of PrP was studied recently in Molecular Simulation Group at ITQB [1] and an evident misfolding transition was observed in one simulation at pH 2. 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. To address this problem, we performed a total of 47 simulations, using our own Constant-pH MD methodology, accounting for a total of 1:25μs. The most significant effect caused by the change to pH 7 is a global stabilization of the protein structure. We observed that some conformational transitions induced by pH 2 were possible to be reverted in many of our simulations, but only in those started from the early moments of the misfolding transition. In other words, if we stop the misfolding process before a major conformational transition takes place, we can revert it. It was not possible to observe a complete reversibility event from a misfolded conformation. Nevertheless, we can not conclude that the transition is irreversible because we can only sample reversible phenomena that happen at sub μs timescale.