Protein flexibility reduces solvent-mediated friction barriers of ligand binding to a hydrophobic surface patch

Solvent fluctuations have been explored in detail for idealized and rigid hydrophobic model systems, but so far it has remained unclear how internal protein motions and their coupling to the surrounding solvent affect the dynamics of ligand binding to biomolecular surfaces. Here, molecular dynamics simulations were used to elucidate the solvent-mediated binding of a model ligand to the hydrophobic surface patch of ubiquitin. The ligand's friction profiles reveal pronounced long-time correlations and enhanced friction in the vicinity of the protein, similar to idealized hydrophobic surfaces. Interestingly, these effects are shaped by internal protein motions. Protein flexibility modulates water density fluctuations near the hydrophobic surface patch and smooths out the friction profile of ligand binding.