LAO+: Focused, Multi-Replica Accelerated Orthogonal Sampling for Robust Binding Free Energy Predictions

We introduce Lambda-ABF-OPES+ ($\text{LAO+}$), a multi-replica framework for absolute binding free energy (ABFE) calculations that accelerates both the alchemical transformation and the slow ``orthogonal'' motions coupled to it. At the core of $\text{LAO+}$ is a partitioned $λ$-dynamics scheme that