Capturing Protein–Ligand Recognition Pathways in Coarse-Grained Simulation

Protein–ligand recognition
is dynamic and complex. A key
approach in deciphering the mechanism underlying the recognition process
is to capture the kinetic process of the ligand in its act of binding
to its designated protein cavity. Toward this end, ultralong all-atom
molecular dynamics simulation has recently emerged as a popular method
of choice because of its ability to record these events at high spatial
and temporal resolution. However, success via this route comes at
an exorbitant computational cost. Herein, we demonstrate that coarse-grained
models of the protein, when systematically optimized to maintain its
tertiary fold, can capture the complete process of spontaneous protein–ligand
binding from bulk media to the cavity at crystallographic precision
and within wall clock time that is orders of magnitude shorter than
that of all-atom simulations. The exhaustive sampling of ligand exploration
in protein and solvent, harnessed by coarse-grained simulation, leads
to elucidation of new ligand recognition pathways and discovery of
non-native binding poses.