Probing the Conformational Ensemble of the Amyloid Beta 16–22 Fragment with Parallel-Bias Metadynamics

Aβ­(16–22) is a segment of the Alzheimer’s-related β-amyloid peptide that plays a crucial role in its aggregation. This study applies well-tempered parallel-bias metadynamics to investigate the impact of several denaturants and osmolytes on the conformational ensembles of both termini-capped and uncapped Aβ(16–22) monomers. Comparison of the different sets of collective variables in the metadynamics bias shows that using the set of backbone torsional angles results in better and faster convergence of simulations than employing more general structural characteristics of the short peptide. The equilibrium conformational ensembles of the peptides are characterized in pure water and in the presence of TMAO, urea, guanidinium chloride, and trifluoroethanol. In particular, trifluoroethanol and TMAO are found to increase the population of compact peptide conformations, whereas urea and guanidinium chloride favor extended structures. The analysis of the free energy surfaces in the presence of various substances with a comparison of the behavior of the capped and uncapped peptide forms reveals the role of different types of intrapeptide interactions such as salt bridges, hydrophobic contacts, and hydrogen bonds in stabilization of the compact or extended structures. As compounds reducing the abundance of the compact states of Aβ(16–22) and other disordered peptides are likely to suppress their amyloid fibril formation, simulations in the systems with this short peptide may be useful for the virtual screening of such compounds.