Figure shows the steps required to set up a QUBE protein force field for a MD simulation. As in Section 2.1, the ONETEP linear-scaling DFT software is used to compute the ground state electron density of the five proteins, and assign the charge and Lennard-Jones parameters from the partitioned atomic electron densities. Consistent with the QUBE small molecule approach, every atom in the protein is assigned bespoke non-bonded parameters derived from the quantum mechanical electron density. To model polarization effects in the condensed phase, the electron density is computed first in vacuum, then using an implicit solvent model with a dielectric constant of 80. The iPol approach used in AMBER ff15ipq is then employed, with all non-bonded parameters set halfway between their vacuum and condensed phase values. The purpose of this approach, as well as overcoming issues associated with closing of the electronic band gap in large system sizes, is to account for electrostatics and induction in the condensed phase in an effective manner using a fixed point charge force field. Typical computational requirements for a QM calculation on a small protein (≈ 1000 atoms) are approximately 2000 cpuhrs. In order to provide a consistent and computationally efficient approach to assigning the non-bonded parameters, we recommend minimizing the experimental structure using a standard transferable force field in explicit water prior to the DFT calculation. In this study, we used the OPLS-AA/M force field for the initial minimization. Following non-bonded parameter assignment, bond, angle and torsion parameters were assigned as described in Section 2 based on the OPLS-AA/M atom types. For torsion and improper types not re-parameterized in this study, OPLS-AA/M parameters are retained. Table summarizes the number of bespoke non-bonded parameters for each protein studied, along with the bonded parameters that are parametrized using the dipeptide molecules as described above. All parameters, including atom-specific non-bonded parameters, are written to a CHARMM-style parameter file. The psf, pdb and inp files are provided in the Supporting Information. We note that preparation of the parameter files is fully automated, and scripts and step-by-step tutorials are available from group/QUBEMAKER. MD simulations were performed using the NAMD software, using input parameters detailed elsewhere (Section S2.1). Statistics were collected over a period of 200 ns for dipeptides and Ala 5 and Gly 3 , and 0.5 µs for the proteins. All MD simulations were performed in triplicate.