Comparisons were also carried out for implicitly and explicitly solvated classical MD for 20 structures from each protein's NMR ensemble. These classical MD simulations were carried out using the AMBER ff14SB force field implemented in the GPU-accelerated version of the AMBER18 code . Explicit water simulations used the TIP3P[141] force field, and at least 20 Å solvent was prepared around the protein using tleap. The Trp-cage protein was neutralized using Cl -, which was modeled with the TIP3P-compatible Cl -parameters implemented in AMBER. In all simulations, both water and protein bonds with hydrogen atoms were fixed using the SHAKE algorithm to afford a timestep of 2 fs. All explicitly solvated classical MD simulations followed the same protocol: i) 1000 steps of restrained minimization, ii) 2000 steps of unrestrained minimization, iii) 10 ps NVT heating to 300 K, and iv) 1 ns of NpT equilibration. A Langevin thermostat with random seed was used for all constant-temperature dynamics with a collision frequency of 5 ps -1 and random seed. Constant-pressure dynamics employed a Berendsen barostat with a rescaling frequency of 2.0 ps -1 . A real-space cutoff of 10 Å was used for particle mesh Ewald summation. Following equilibration, NpT production dynamics were carried out for 250 ns.