Optimization of Alchemical Pathways Using Extended Thermodynamic Integration

Thermodynamic integration (TI) is a commonly used method to determine free-energy differences. One of its disadvantages is that many intermediate lambda-states need to be sampled in order to be able to integrate accurately over . Here, we use the recently introduced extended TI to study alternative parameterizations of H(lambda) and its influence on the smoothness of the curves as well as the efficiency of the simulations. We find that the extended TI approach can be used to select curves of low curvature. An optimal parameterization is suggested for the calculation of hydration free energies. For calculations of relative binding free energies, we show that optimized parameterizations of the Hamiltonian in the unbound state also effectively lower the curvature in the bound state of the ligand.

Automated summary

The extended TI method can be used to select curves of low curvature, improving simulation efficiency. For hydration free energy calculations, an optimal parameterization is recommended. In calculations of relative binding free energies, optimized parameterizations of the Hamiltonian can effectively lower the curvature in the bound state of the ligand.