Long-range electrostatics were treated with the PME scheme with a 1.2 nm cutoff, a grid spacing of 0.1 nm and a 4th order interpolation. The Monte Carlo barostat was used with a relaxation time of 1 ps for an isotropic coupling of system pressure to 1 bar; temperature coupling was handled by the leap-frog Langevin integrator with a collision frequency of 1 ps 1 . Simulations for the calculation of the input parameters in Equation 1 in the main text followed the same protocol except that no restraints were imposed on the backbone atoms; these trajectories were used as input for the APBS 20 software to estimate the electrostatic hydration free energy of the amino acids using the linearized Poisson-Boltzmann equation, as described in more detail below.