In creating fragments, we avoid cutting the polar C-N peptide bond (following previous recommendations), and instead create fragments by cutting the C-C bond at C α , as indicated in Fig. . The severed valency is capped with a hydrogen atom that is positioned according to eq. S1, as in previous work. All QM calculations were run using a home-built interface (PyFragme∩t) to Q-Chem. 107 For all calculations, the self-consistent field convergence threshold is set to τ SCF = 10 -8 Ha and the integral and shell-pair drop tolerances are set to τ ints = 10 -12 a.u. We use the conductor-like PCM (C-PCM), implemented with the switching/Gaussian discretization scheme. The continuum interface is defined by a van der Waals cavity, constructed using modified Bondi atomic radii 112 that are scaled by a factor of 1.2. That surface is discretized using 110 Lebedev points for hydrogen and 194 points for other atoms. A conjugate gradient algorithm was used to solve the C-PCM equations for the full protein model, 111 whereas matrix inversion was used for the subsystem C-PCM calculations. Calculations with ωB97X-D and M06-2X+D3 use the SG-2 quadrature grid, 113 whereas SG-1 114 is used for other functionals.