Computational investigation of conformational fluctuations of Aβ42 monomers in aqueous ionic liquid mixtures

Abstract

Aggregation of intrinsically disordered proteins (IDPs) is often triggered by protein–protein interaction, leading to several neurodegenerative diseases.In this study, we aim to understand the role of 1-butyl-3-methylimidazolium tetrafluoroborate [BMIM][BF4] ionic liquid (IL) on altering secondary structure of the peptide and study the interactions responsible for their conformational modification. Here we report structural features of an ensemble of amyloid beta (Aβ42) peptide monomers employing all-atom molecular dynamics simulations in aqueous solution of IL at room temperature. Our calculations reveal, Aβ42 peptide exhibit rapidly inter-converting conformations adopting extended chain as well as collapsed coil-like structures with a propensity to form few transient α-helices and β-sheets at intermediate times. We have correlated this higher flexibility of the peptide with formation of less stable salt-bridge in presence of IL in aqueous solution. It is found that water molecules around the polar regions are more structured imparting structural rigidity to the peptide backbone than around the hydrophobic domains. Thus identifying the effect of electrostatic interaction of IL on expulsion of water molecules from the polar domains on the peptide surface can shed light on preventing the aggregation process. We have also determined the most energetically stable peptide conformations from various accessible intermediate states using metadynamics simulations that are characterized by the rugged free energy surface having multiple energy basins.