Following parameterization, equilibration stages were run using OpenMM 64-66 (version 7.1.1), followed by production free energy calculations done with Yank (version 0.20.1), using protocols that are now relatively standard (e.g. as in ). Nonbonded interactions were calculated for all inter-atomic distances under a cutoff of 9 Å. Electrostatic interactions were computed using particle mesh Ewald (PME). Each Hamiltonian replica exchange simulation run using Yank had 1000 iterations of 500 MD steps of 2 femtoseconds each at each λ value, totaling one nanosecond per replica. Bonds involving hydrogen were constrained.