Each system was minimized with all heavy protein atoms restrained at their initial positions (with a restraining force constant of 4 kcal mol -1 Å -2). Initial velocities were then generated independently for each replica from a Maxwell-Boltzmann distribution at 50 K. Each system was virtually heated to 300 K over 60 ps and subsequently maintained at this temperature using a thermostat (employing a coupling coefficient of 1 ps-1) during which time the restraints applied during minimization were retained. Once the system reached the correct temperature the pressure was maintained at 1 bar using a Berendesen barostat (with a pressure coupling constant of 0.1 ps). Subsequent to the heating, a series of equilibration runs, totaling 2 ns, were conducted, during which the restraints on heavy atoms were gradually reduced. The restraint reduction occurs in ten 100 ps steps, after each one the force constant was halved. Finally, 4 ns production simulations were executed with snapshots output for analysis every 100 ps. A 2 fs time step was used for all MD simulation steps. An overview of the ESMACS workflow is provided in the additional information section at the end of this document.