License (LGPL) version 3, or any later version, as published by the Free Software Foundation (FSF). The CPMD interface will be in a forthcoming release of CPMD but patches for the current release can be obtained from the corresponding author, while the interface in bration while the remainder was used for further analysis. While this was adequate for the solute-solvent systems, it was not enough to fully equilibrate the GB1 system. The latter half was used regardless since it does not affect the analyses performed in this work. In these simulations, the short-range coupling was used for all MM atoms in the Wat(aq) and Ace(aq) systems while the long-range coupling was employed for the BuOH(ace) and GB1 systems. The BuOH(ace) system was partitioned into short-and long-range domains using the fragment-based scheme with a cutoff distance of 32 a.u. and using a fifth-order multipole expansion for the long-range coupling. For the GB1 system, we used the atom-based partitioning with a cutoff distance of 36 a.u. and a seventh-order multipole expansion for the long-range coupling. In both cases, the list of short-and long-range atoms was updated every 50th step. The temperature was initialized at 300 K and was subsequently maintained with a Nosé-Hoover chain thermostat 52 using a chain length of 4 and a frequency of 3500 cm -1 for the Wat(aq) system and 3000 cm -1 for the Ace(aq), BuOH(ace), and GB1 sys-tems. In the case of the solute-solvent systems, the MM subsystem was modeled using the optimized potential for liquid simulations all-atom (OPLS/AA) force field, employing the transferable intermolecular potential with three points (TIP3P) water model and topologies of acetone and n-butanol that were downloaded from the GROMACS Molecule & Liquid Database (). The MM subsystem of GB1 was modeled using the AMBER ff14SB 57 force field. The bonds of all classical water molecules in the Wat(aq), Ace(aq), and GB1 systems were constrained using the SHAKE algorithm. The simulation cell dimensions were set according to the final dimensions obtained from and NPT MM-MD simulations in the preequilibration procedure (see details in the SI). We thus used cubic cells with lengths of 58.67, 58.66, and 225.8 a.u. for Wat(aq), Ace(aq), and BuOH(ace), respectively, and an orthorhombic cell for GB1 with lengths of 121.3, 120.4, and 121.2 a.u.