Dynamics of Disordered Proteins under Confinement: Memory Effects and Internal Friction.

Abstract

Many proteins are disordered under physiological conditions. How efficiently they can search for their cellular targets and how fast they can fold upon target binding is determined by their intrinsic dynamics, which have thus attracted much recent attention. Experiments and molecular simulations show that the inherent reconfiguration timescale for unfolded proteins has a solvent friction component and an internal friction component, and the microscopic origin of the latter, along with its proper mathematical description, has been a topic of considerable debate. Internal friction varies across different proteins of comparable length and increases with decreasing denaturant concentration, showing that it depends on how compact the protein is. Here we report on a systematic atomistic simulation study of how confinement, which induces a more compact unfolded state, affects dynamics and friction in disordered peptides. We find that the average reconfiguration timescales increase exponentially as the peptide's spatial dimensions are reduced; at the same time, confinement broadens the spectrum of relaxation timescales exhibited by the peptide. There are two important implications of this broadening: First, it limits applicability of the common Rouse and Zimm models with internal friction, as those models attempt to capture internal friction effects by introducing a single internal friction timescale. Second, the long-tailed distribution of relaxation times leads to anomalous diffusion effects in the dynamics of intramolecular distances. Analysis and interpretation of experimental signals from various measurements that probe intramolecular protein dynamics (such as single-molecule fluorescence correlation spectroscopy and single-molecule force spectroscopy) rely on the assumption of diffusive dynamics along the distances being probed; hence, our results suggest the need for more general models allowing for anomalous diffusion effects.