Study of the pH-dependent misfolding of human prion protein by constant-pH molecular dynamics simulations

ITQB PhD SEMINAR

Title: Study of the pH-dependent misfolding of human prion protein by constant-pH molecular dynamics simulations

Speaker: Sara Campos

Laboratory: Molecular Simulation, ITQB

Abstract

 Prion proteins (PrP) are the cause of transmissible spongiform encephalopathies such as Creutzfeldt-Jakob disease in humans or bovine spongiform encephalopathy in cattle. The normal form of PrP (PrPC) is monomeric and soluble but it can be transformed into a pathogenic beta-rich form (PrPSc) which aggregates and forms amyloid fibrils. This transition can be catalysed by a PrPSc template, according to the "protein-only hypothesis", or it can be spontaneous [1]. The conversion can be induced by acidic pH and is thought to occur in the endocytic pathway [2].
In this work we performed constant-pH molecular dynamics [3] of human PrP 90-231 at pH 2, 4, 5, 6 and 7. A total of 60 simulations, accounting for 2,04 µs of simulation time, was performed.
We observed a strong conformational pH-dependence where on average the helix content decreased and the beta content increased towards acidic pH. Unlike some proposed models [4], the flexible N-terminal did not gain structure at low pH and the main structural changes occurred on the helix-rich C-terminal core, namely in the regions corresponding to helix A up to beta-strand 1 and C-terminal helix B up to helix C. In one of the simulations at pH 2, a beta-rich structure was formed, proving that this type of transition may occur prior to dimerisation.
 

Short CV

2000-2004: Degree in Biochemistry by Faculdade de Ciências e Tecnologia da Universidade de Coimbra.
2005: Research student in the Molecular Simulation group at ITQB, under the supervision of Dr. António M. Baptista.
Since January of 2006: PhD student in the Molecular Simulation group at ITQB, under the supervision of Dr. António M. Baptista. Research area: study of the electrostatic effects on protein structure using computational methods.