Machine Learning and Enhanced Sampling Simulations for Computing the Potential of Mean Force and Standard Binding Free Energy

Computational capabilities are rapidly increasing, primarily because of the availability of GPU-based architectures. This creates unprecedented simulative possibilities for the systematic and robust computation of thermodynamic observables, including the free energy of a drug binding to a target. In contrast to calculations of relative binding free energy, which are nowadays widely exploited for drug discovery, we here push the boundary of computing the binding free energy and the potential of mean force. We introduce a novel protocol that leverages enhanced sampling, machine learning, and ad hoc algorithms to limit human intervention, computing time, and free parameters in free energy calculations. We first validate the method on a host-guest system, and then we apply the protocol to glycogen synthase kinase 3 beta, a protein kinase of pharmacological interest. Overall, we obtain a good correlation with experimental values in relative and absolute terms. While we focus on protein-ligand binding, the strategy is of broad applicability to any complex event that can be described with a path collective variable. We systematically discuss key details that influence the final result. The parameters and simulation settings are available at PLUMED-NEST to allow full reproducibility.

Automated summary

The computational capabilities are rapidly increasing due to the availability of GPU-based architectures, creating unprecedented simulative possibilities for the systematic computation of thermodynamic observables. A novel protocol leveraging enhanced sampling, machine learning, and ad hoc algorithms is introduced to limit intervention, computing time, and free parameters in free energy calculations. The method shows good correlation with experimental values and can be reproducible in a broad range of complex events.