Capturing Protein-Ligand Recognition Pathways in Coarse-grained Simulation

Protein-substrate recognition is highly dynamic and complex process in nature. A key approach in deciphering the mechanism underlying the recognition process is to capture the kinetic process of substrate in its act of binding to its designated protein cavity. Towards this end, microsecond long atomistic molecular dynamics (MD) simulation has recently emerged as a popular method of choice, due its ability to record these events at high spatial and temporal resolution. However, success in this approach comes at an exorbitant computational cost. Here we demonstrate that coarse grained models of protein, when systematically optimised to maintain its tertiary fold, can capture the complete process of spontaneous protein-ligand binding from bulk media to cavity, within orders of magnitude shorter wall clock time compared to that of all-atom MD simulations. The simulated and crystallographic binding pose are in excellent agreement. We find that the exhaustive sampling of ligand exploration in protein and solvent, harnessed by coarse-grained simulation at a frugal computational cost, in combination with Markov state modelling, leads to clearer mechanistic insights and discovery of novel recognition pathways. The result is successfully validated against three popular protein-ligand systems. Overall, the approach provides an affordable and attractive alternative of all-atom simulation and promises a way-forward for replacing traditional docking based small molecule discovery by high-throughput coarse-grained simulation for searching potential binding site and allosteric sites. This also provides practical avenues for first-hand exploration of bio-molecular recognition processes in large-scale biological systems, otherwise inaccessible in all-atom simulations.