Fast protein folding is governed by memory-dependent friction

TL;DR

This study uses a generalized Langevin equation approach to directly measure memory-dependent friction in protein folding, revealing its dominant role over free-energy barriers and its impact on folding times.

Contribution

It introduces a method to directly compute memory-dependent friction in protein folding, highlighting its significance over free-energy barriers in folding rate determination.

Findings

Friction plays a more crucial role than free energy barriers in folding rates.

Finite decay time of friction can reduce folding times by up to tenfold.

Memory effects significantly influence protein folding dynamics.

Abstract

When described by a low-dimensional reaction coordinate, the rates of protein folding are determined by a subtle interplay between free-energy barriers and friction. While it is commonplace to extract free-energy profiles from molecular trajectories, a direct evaluation of friction is far more elusive, and one typically evaluates it indirectly via memoryless reaction rate theories. Here, using memory-kernel extraction methods founded on a generalised Langevin equation (GLE) formalism, we directly calculate the memory-dependent friction for eight fast-folding proteins, taken from a published set of large-scale molecular dynamics protein simulations. Our results reveal that, contrary to common expectation, friction is more important than free energy barriers in determining protein folding rates, particularly for larger proteins. We also show that proteins fold in a regime where the finite decay time of friction significantly reduces the folding times, in some instances by as much as a factor of 10, compared to predictions based on memoryless friction.