Acknowledgement DLM and SCG appreciate the financial support from the National Science Foundation (CHE 1352608) and the National Institutes of Health (1R01GM108889-01) and computing support from the UCI GreenPlanet cluster, supported in part by NSF Grant CHE-0840513. JDC appreciates support from the Sloan Kettering Institute and NIH grant P30 758 CA008748. We appreciate helpful discussions with Christopher I. Bayly (OpenEye Scientific Software) and Ioan Andricioaei (UC Irvine). We also appreciate the anonymous reviewer who suggested that our protocol work values could be useful to obtain free energy estimates, not just as part of the acceptance criterion.