Probing the Conformational\nEnsemble of the Amyloid\nBeta 16–22 Fragment with Parallel-Bias Metadynamics

Aβ(16–22) is a segment of the Alzheimer’s-related\nβ-amyloid peptide that plays a crucial role in its aggregation.\nThis study applies well-tempered parallel-bias metadynamics to investigate\nthe impact of several denaturants and osmolytes on the conformational\nensembles of both termini-capped and uncapped Aβ(16–22)\nmonomers. Comparison of the different sets of collective variables\nin the metadynamics bias shows that using the set of backbone torsional\nangles results in better and faster convergence of simulations than\nemploying more general structural characteristics of the short peptide.\nThe equilibrium conformational ensembles of the peptides are characterized\nin pure water and in the presence of TMAO, urea, guanidinium chloride,\nand trifluoroethanol. In particular, trifluoroethanol and TMAO are\nfound to increase the population of compact peptide conformations,\nwhereas urea and guanidinium chloride favor extended structures. The\nanalysis of the free energy surfaces in the presence of various substances\nwith a comparison of the behavior of the capped and uncapped peptide\nforms reveals the role of different types of intrapeptide interactions\nsuch as salt bridges, hydrophobic contacts, and hydrogen bonds in\nstabilization of the compact or extended structures. As compounds\nreducing the abundance of the compact states of Aβ(16–22)\nand other disordered peptides are likely to suppress their amyloid\nfibril formation, simulations in the systems with this short peptide\nmay be useful for the virtual screening of such compounds.