pH Modulates Friction Memory Effects in Protein Folding

Abstract

Protein folding is an intrinsically multitimescale problem. While it is accepted that non-Markovian effects are present on short timescales, it is unclear whether memory-dependent friction influences long-timescale protein folding reaction kinetics. We combine friction memory-kernel extraction techniques with recently published extensive all-atom simulations of the 𝛼⁢3⁢D protein under neutral and reduced pH conditions, and we show that the pH reduction modifies the friction acting on the folding protein by dramatically decreasing the friction memory decay time. This switches 𝛼⁢3⁢D folding reaction kinetics from the pronounced non-Markovian regime, where memory significantly accelerates folding, to the Markovian regime, where memory does not influence the folding time. We explore salt-bridge interactions, which are eliminated under pH reduction, as a key microscopic origin of non-Markovian friction in 𝛼⁢3⁢D.