Protein-protein binding pathways and calculations of rate constants using fully continuous explicit solvent simulations

Abstract

A grand challenge in the field of biophysics has been the complete characterization of proteinprotein binding processes at atomic resolution. This characterization requires the direct simulation of binding pathways starting from the initial unbound state and proceeding through states that are too transient to be captured by experiment. Here we applied the weighted ensemble path sampling strategy to enable atomistic simulation of protein-protein binding pathways. Our simulation generated 203 fully continuous binding pathways for the bacterial proteins, barnase and barstar, yielding a computed kon that is within error of experiment. Results reveal that the formation of the "encounter complex" intermediate is rate limiting with ~11% of all diffusional collisions being productive. Consistent with experiment, our simulations identify R59 as the most kinetically important barnase residue for the binding process. Furthermore, protein desolvation occurs late in the binding process during the rearrangement of the encounter complex to the native complex. Notably, the positions of interfacial crystallographic water molecules that bridge hydrogen bonds between barnase and barstar are occupied upon formation of the native complex in our simulations. Our simulations were completed within a month using 1600 CPU cores at a time, demonstrating that it is now practical to carry out atomistic simulations of protein-protein binding processes, particularly using the latest GPU-accelerated computing.

Investigations of Albumin–Insulin Detemir Complexes Using Molecular Dynamics Simulations and Free Energy Calculations

“…These findings are not contradictory, as hydrophobic interactions are generally found to be the driving interactions in protein-protein complexes, whereas the long-range electrostatic interactions are steering in the complex formation and contribute to interaction specificity. 90,[99][100][101] In agreement with the results of Fatima et al 20 , we have found that addition of NaCl promotes complex formation (Supplementary Figure S19), which indicates that hydrophobic interactions stabilize the albumin-detemir complex.…”

A glycan gate controls opening of the SARS-CoV-2 spike protein

“…Given that these transitions are much faster than the waiting times, 16,17 the WE strategy can be orders of magnitude more efficient than conventional MD simulations in generating pathways for rare events such as protein folding and protein binding. 18,19 This efficiency is even higher for slower processes, increasing exponentially with the effective free energy barrier. 20 Not only are dynamics carried out without any biasing force or modifications to the free energy landscape, but suitable assignment of statistical weights to trajectories provides an unbiased characterization of the system’s time-dependent ensemble properties.…”

Exploring ligand binding pathways on proteins using hypersound–accelerated molecular dynamics

“…This study shows that hypersound-stimulated MD simulations have the potential to accelerate proteinligand binding kinetics through a solvent-mediated mechanism without collapse of the protein structure, thus enabling atomic-scale observation of ligand-binding processes within time scales accessible by standard MD (~ 100 ns). In contrast to other advanced MD methods that accelerate biomolecular processes 25,26 , this method does not require prior knowledge of the protein-ligand complex structure. In this way, the simulations can provide signi cant insights into fundamental biological mechanisms (such as the discovery of microscopic ligand binding pathways involving various bound conformations) and facilitate drug discovery (as illustrated by the present exploration of druggable binding sites on the protein surface).…”