The reacting region was described using the same valence bond states and EVB parameters as in prior work. For each system, we performed six individual sets of REMD-EVB simulations: 5 runs of 10 ps length per λ window (5 x 10), 5 runs of 20 ps length per λ window (5 x 20), 10 runs of 10 ps length per λ window (10 x 10), 10 runs of 20 ps length per λ window (10 x 20), 10 runs of 100 ps length per λ window (10 x 100), and 10 runs of 200 ps length per λ window . This leads to total simulation times of 25.5 ns for our (5x10), 51 ns for our (5x20), 51 ns for our (10 x 10), 102 ns for our (10 x 20), 510 ns for our (10 x 100) and 1020 ns for our (10 x 200) runs over 10 replicas. We also performed conventional EVB simulations 51 x 20 ps (with a total simulated time of 10.2 ns) and 51 x 200 ps (with a total simulated time of 102 ns) runs per replica, again 10 replicas for comparison, using the same initial equilibration runs as for the REMD-EVB runs. All energy analysis was performed using the Qfep module of the Q6 software package . For further simulation details, see Refs. .