In MD simulations using the new-rf input parameters and various combinations of lincs order and time step, we found that all differences between the solute temperature and the thermostat reference temperature were less than 1.5 K, and that the temperature difference between the solute and the solvent never exceeded 2 K (Tables ). Interestingly, "flipping" the diagonal constraint in the molecular topologies did not produce a clear improvement (Tables ), most likely due to the only moderately large λ max values.