Host–Guest\nBinding Free Energies a la\nCarte: An Automated OneOPES Protocol

Estimating absolute binding free energies from molecular\nsimulations\nis a key step in computer-aided drug design pipelines, but the agreement\nbetween computational results and experiments is still very inconsistent.\nBoth the accuracy of the computational model and the quality of the\nstatistical sampling contribute to this discrepancy, yet disentangling\nthe two remains a challenge. In this study, we present an automated\nprotocol based on OneOPES, an enhanced sampling method that exploits\nreplica exchange and can accelerate several collective variables to\naddress the sampling problem. We apply this protocol to 37 host–guest\nsystems. The simplicity of setting up the simulations and producing\nwell-converged binding free energy estimates without the need to optimize\nsimulation parameters provides a reliable solution to the sampling\nproblem. This, in turn, allows for a systematic force field comparison\nand ranking according to the correlation between simulations and experiments,\nwhich can inform the selection of an appropriate model. The protocol\ncan be readily adapted to test more force field combinations and study\nmore complex protein–ligand systems, where the choice of an\nappropriate physical model is often based on heuristic considerations\nrather than systematic optimization.