Finding the true Binding Free Energy remains a crucial challenge in computer-aided drug design, even for simple systems. Molecular dynamics-based alchemical binding free energy calculations are increasingly being used in academic and industrial settings for this purpose. The reliability of the predictions of these calculations depends on many factors including the representation of the relevant chemical states and the accuracy of the energy function. The proper sampling of the main conformations of the system is increasingly seen as a critical aspect. However, the thorough sampling of ligand conformations, for example, can be difficult within an affordable computational time especially when there are large free energy barriers separating the major ligand conformations. Here, we illustrate the application of a metadynamics-based approach to accelerate the sampling of intramolecular degrees of freedom in the context of the Alchemical Transfer Method (ATM). Specifically, we achieve enhanced sampling by introducing a biasing potential, obtained by metadynamics, that flattens the conformational landscape of the ligand in solution along chosen reaction coordinates; typically dihedral angles. The unbiased binding free energy is then obtained from the biased simulation using a thermodynamic reweighting procedure. We show that the metadynamics-ATM approach improves the convergence rate and the reliability of alchemical binding free energy estimates, especially for systems where the ligand undergoes binding-induced conformational reorganization.

Metadynamics-based approach for the sampling of intramolecular degrees of freedom in alchemical binding free energy calculations

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