Figure summarizes the performance characteristics of our implementation for both the ML/MM, and the simpler ML/MM (ME) coupling modes. Simulations were performed across different ML region sizes, using an RTX 2080 Ti GPU, on an Intel Core i9 CPU (9900K), with sander MPI utilizing up to 8 CPU cores. We observed that increasing the number of CPU cores beyond this threshold did not yield significant relative speed-ups either for MM or ML/MM simulations, suggesting that Sander's MPI gives optimal results with this configuration, for this particular model system. An estimated percentage of computational cost attributed to the ML subsystem is also shown, which was derived by comparison with full MM simulations (MM/MM). As 5, panel B shows, with 8 cores the cost associated with our ML/MM implementation is around 3 times that of a purely MM simulation. We emphasize, however, that ML/MM is significantly less costly than established QM/MM approaches, which can't easily access nanosecond timescales.