David L. Mobley, Michael K. Gilson
Binding free energy calculations based on molecular simulations provide predicted affinities for biomolecular complexes. These calculations begin with a detailed description of a system, including its chemical composition and the interactions between its components. Simulations of the system are then used to compute thermodynamic information, such as binding affinities. Because of their promise for guiding molecular design, these calculations have recently begun to see widespread applications in early stage drug discovery. However, many challenges remain to make them a robust and reliable tool. Here, we briefly explain how the calculations work, highlight key challenges, and argue for the development of accepted benchmark test systems that will help the research community generate and evaluate progress.