Obtaining the partial charges for the partially fluorinated amino acids required initial simulations of single copies of the amino acids (with non-optimized charges) in water, to obtain multiple configurations that were then used in the multi-configuration RESP fit, as described in ref. 3. The simulation boxes used for each type of simulation are illustrated in SI Figure ; periodic boundary conditions in all directions were used in all cases. All systems were assembled using the built-in tools of the software package used to perform the simulations. A summary of the most relevant parameters used during the production runs is given in SI Table . Simulations used a time-step of 2 fs and constraints (LINCS 15 in Gromacs, SHAKE in Amber) were applied to all bonds involving hydrogen atoms. Integration of the equations of motion was done using a leap-frog Langevin algorithm. Van der Waals interactions were shifted to zero between 1.0 and 1.2 nm, and long-range dispersion corrections were applied to both pressure and energy. For the parameterization of the Lennard-Jones s H F and e H F , each FEP and liquid phase simulation (molar volume and enthalpy of vaporization) consisted of a steepest-descent minimization, BFGS minimization, 100 ps of NVT equilibration, 100 ps of NpT equilibration and production run; gas phase simulations (enthalpy of vaporization) consisted only of the production run. FEP simulation of the amino acids also used the same equilibration procedure. Production runs were done in the NpT ensemble (liquid simulations) or the NVT ensemble (for gas phase). Long-range electrostatics were treated with the PME 17 scheme with a 1.2 nm cutoff, a grid spacing of 0.12 nm and a 6th order interpolation. The Berendsen barostat 18 was used with a time constant of 1 ps for coupling pressure to 1 bar; temperature coupling was enforced in the leap-frog Langevin integrator with a time constant of 1 ps.