PopShift: A thermodynamically sound approach to estimate binding free energies by accounting for ligand-induced population shifts from a ligand-free MSM

Obtaining accurate binding free energies from in silico screens has been a longstanding goal for the computational chemistry community. However, accuracy and computational cost are at odds with one another, limiting the utility of extant approaches. Many methods achieve scale by assuming that the target protein adopts a single structure, or undergoes limited fluctuations around that structure. Others simulate each protein-ligand complex of interest, accepting lower throughput in exchange for better predictions of binding affinities.