An Approach to Alchemical Binding Free-Energy Calculations Using Coupled Topologies

We present an approach to performing alchemical binding free energies which we term coupled topologies. Simultaneously coupling a molecule in the bound state while decoupling it in the unbound state allows us to calculate free energy changes where the system changes charge, without the need to correct for simulation artifacts. This solves a longstanding problem in computing free energy changes. The approach is applied to separated topology relative binding free energy calculations, but is appropriate for single topology calculations and dual topology calculations as well as absolute binding free energy calculations. We apply the method to small-molecule inhibitors of AmpC β-lactamase and show the coupled topologies approach yields results that are in excellent agreement with experiment and good agreement with a state-of-the-art separated topology approach. The promising results on this test case suggest that the coupled topologies approach will be a useful addition to the available arsenal of free-energy methods.