Impact of Hydrodynamic Interactions on the Kinetic Pathway of Protein Folding

Protein folding is a fundamental process critical to cellular function and human health, but it remains a grand challenge in biophysics. Hydrodynamic interaction (HI) plays a vital role in the self-organization of soft and biological materials, yet its role in protein folding is not fully understood despite folding occurring in a fluid environment. Here, we use the fluid particle dynamics method to investigate many-body hydrodynamic couplings between amino acid residues and fluid motion in the folding kinetics of a coarse-grained four-α-helices bundle protein. Our results reveal that HI helps select fast folding pathways to the native state without being kinetically trapped, significantly speeding up the folding kinetics compared to its absence. First, the directional flow along the protein backbone expedites protein collapse. Then, the incompressibility-induced squeezing flow effects retard the accumulation of non-native hydrophobic contacts, thus preventing the protein from being trapped in local energy minima during the conformational search of the native structure. We also find that the significance of HI in folding kinetics depends on temperature, with a pronounced effect under biologically relevant conditions. Our findings suggest that HI, particularly the short-range squeezing effect, may be crucial in avoiding protein misfolding.