The impact of hydrodynamic interactions on protein folding rates depends on temperature

TL;DR

This study explores how hydrodynamic interactions influence protein folding rates, revealing a temperature-dependent crossover effect where HI can either slow down or speed up folding depending on the temperature relative to the folding temperature.

Contribution

It demonstrates the temperature-dependent impact of hydrodynamic interactions on protein folding kinetics using coarse-grained models and energy landscape theory.

Findings

HI slows folding above the folding temperature due to increased friction.

Below the folding temperature, HI accelerates folding via solvent backflow.

Protein topology influences the extent of HI's effect on folding rates.

Abstract

We investigated the impact of hydrodynamic interactions (HI) on protein folding using a coarse-grained model. The extent of the impact of hydrodynamic interactions, whether it accelerates, retards, or has no effect on protein folding, has been controversial. Together with a theoretical framework of the energy landscape theory (ELT) for protein folding that describes the dynamics of the collective motion with a single reaction coordinate across a folding barrier, we compared the kinetic effects of HI on the folding rates of two protein models that use a chain of single beads with distinctive topologies: a 64-residue alpha/beta chymotrypsin inhibitor 2 (CI2) protein, and a 57-residue beta-barrel alpha-spectrin src-Homology 3 domain (SH3) protein. When comparing the protein folding kinetics simulated with Brownian dynamics in the presence of HI to that in the absence of HI, we find that the effect of HI on protein folding appears to have a crossover behavior about the folding temperature. Meaning that at a temperature greater than the folding temperature, the enhanced friction from the hydrodynamic solvents between the beads in an unfolded configuration results in lowered folding rate; conversely, at a temperature lower than the folding temperature, HI accelerates folding by the backflow of solvent toward the native folded state. Additionally, the extent of acceleration depends on the topology of a protein: for a protein like CI2, where its folding nucleus is rather diffuse in a transition state, HI channels the formation of contacts by favoring a major folding pathway in a complex free energy landscape, thus accelerating folding. For a protein like SH3, where its folding nucleus is already specific and less diffuse, HI matters less at a temperature lower than the folding temperature. Our findings provide further theoretical insight to protein folding kinetic experiments and simulations.