Lambda-ABF-OPES: Faster Convergence with High Accuracy in Alchemical Free Energy Calculations

Predicting the binding affinity between small molecules and target macromolecules while combining both speed and accuracy is a cornerstone of modern computational drug discovery, which is critical for accelerating therapeutic development. Despite recent progress in molecular dynamics (MD) simulations, such as advanced polarizable force fields and enhanced sampling techniques, estimating absolute binding free energies (ABFEs) remains computationally challenging. To overcome these difficulties, we introduce a highly efficient hybrid methodology that couples the Lambda-adaptive biasing force (Lambda-ABF) scheme with on-the-fly probability enhanced sampling (OPES). This approach achieves up to a 9-fold improvement in sampling efficiency and computational speed compared to the original Lambda-ABF when used in conjunction with the AMOEBA polarizable force field, yielding converged results at a fraction of the cost of standard techniques.