pH modulates friction memory effects in protein folding

TL;DR

This study shows how pH levels influence protein folding dynamics by modulating friction and memory effects, revealing that low pH simplifies the process to a Markovian model while neutral pH involves significant non-Markovian behavior.

Contribution

It provides the first direct evaluation of how pH-induced changes in salt-bridge interactions affect non-Markovian friction and folding kinetics in proteins.

Findings

Lower pH reduces friction magnitude and shortens memory time scales.

Low pH folding dynamics are well described by Markovian models.

Neutral pH exhibits significant non-Markovian effects with a sixfold faster barrier crossing.

Abstract

We study the non-Markovian folding dynamics of the $\alpha$3D protein under low- and neutral-pH conditions. Recently published all-atom simulations of $\alpha$3D by the Shaw group reveal that lowering the pH significantly reduces both native and non-native salt-bridge interactions, which dominate the folding dynamics. Here, we demonstrate that this physiochemical modulation directly perturbs the folding friction, which we evaluate using non-Markovian memory-kernel-extraction techniques. In doing so, we find that the reduction in pH not only decreases the magnitude of the time-dependent friction acting on the protein but also more dramatically shortens the time scale of the friction memory effects. As a result, the folding dynamics in the low pH system are well described by a purely Markovian model. In the neutral pH system, however, the memory time scale is of the same order as the folding time and is accelerated by a factor of 6 compared to a Markovian model prediction. We demonstrate that this memory-induced barrier-crossing speed-up is predicted by non-Markovian reaction-kinetic theories, confirming that non-Markovian models are, in general, necessary for a quantitative description of protein folding dynamics.