Effects of Confinement on the Structure and Dynamics of an Intrinsically Disordered Peptide: A Molecular-Dynamics Study

Abstract

In vivo, proteins and peptides are exposed to radically different environments than those in bulk. Because of the abundance of other cellular components, proteins perform their function in crowded and confined spaces. Confinement has been shown to alter the structure, dynamics, and folding of proteins that possess a native fold. Little is known, however, of the effects of confinement on biologically important intrinsically disordered proteins or peptides (IDP). Here, we use extensive molecular dynamics simulations to investigate the effects of confinement in an IDP, the Aβ21-30, a central folding nucleus of the full length amyloid β-protein. In this study, we report results derived from 107 μs of molecular dynamics simulations that subjected the Aβ21-30 to two types of confinement: hydrophilic and hydrophobic pores. Results show that turn structures are enhanced as a function of decreasing pore size (increasing confinement) over other structures, including coils, β-hairpins, and bridges. However, the percentage occurrence of the dominant hydrogen bond between amino acids Asp23 and Ser26 shown to stabilize the turn in bulk simulations does not increase as a function of confinement signifying a disconnect between structure and internal hydrogen bonding. Differences in structure and dynamics of the decapeptide due to hydrophilic and hydrophobic confinement are more apparent at the extreme confinement conditions, where a reduction of the available phase space in hydrophilic confinement is explained in terms of interactions between the decapeptide and a layer of water at the interface between the decapeptide and the surface of the pore, and a smaller size of the decapeptide in the hydrophobic pores is rationalized in terms of peptide-surface interactions.