Effect of a point mutation on the conformational ensemble of an intrisecally disordered peptide: a molecular dynamics study on Amyloid-β

Abstract

Intrinsically Disordered Peptides (IDPs) are proteins without a well-defined 3D structure. They range from completely unstructured polypeptides to extended partially structured forms and even collapsed states in a heterogeneous conformational ensemble. These proteins are abundant in nature and, despite their lacking of a definite structure, they perform vital functions. As IDPs play a crucial role in numerous biological processes, many of these proteins are implicated in human diseases. For example Amyloid-β (Aβ) is an IDP, which is involved in the Alzheimer’s Disease (AD). We analyze the conformational ensemble of Aβ40 and 42, the two most common species of Aβ in AD, at 311 K and of two mutants of the 42-long peptide, the Flemish and the Dutch. We also study from a computational and biophysical point of view the effect of a point mutation on an IDP, showing that it can causes dramatic effects in the energy landscape, in contrast with the case of structured proteins. In fact, we experiment with a new approach to build the mutant ensembles starting from the wild type (WT) case. We perform many molecular dynamic simulations and address the issue of convergence, which is fundamental in the case of IDPs.