Further Optimization and Validation of the Classical Drude Polarizable Protein Force Field.

The CHARMM Drude-2013 polarizable force field (FF) was developed to include the explicit treatment of induced electronic polarizability, resulting in a more accurate description of the electrostatic interactions in molecular dynamics (MD) simulations. While the Drude-2013 protein FF has shown success in improving the folding properties of alpha-helical peptides and to reproduce experimental observables in simulations up to 1 mus, some limitations were noted regarding the stability of beta-sheet structures in simulations longer than 100 ns as well as larger deviations from crystal structures in simulations of a number of proteins compared to the additive CHARMM36 protein FF. The origin of the instability has been identified and appears to be primarily due to overestimated atomic polarizabilities and induced dipole-dipole interactions on the Cbeta, Cgamma and Cdelta side chain atoms. To resolve this and other issues, a number of aspects of the model were re-visited, resulting in Drude-2019 protein FF. Backbone parameters were optimized targeting the conformational properties of the (Ala)5 peptide in solution along with gas phase properties of the alanine dipeptide. Dipeptides that contain N-acetylated and N'-methylamidated termini, excluding Gly, Pro and Ala, were used as models to optimize the atomic polarizabilities and Thole screening factors on selected Cbeta, Cgamma and Cdelta carbons by targeting quantum mechanical (QM) dipole moments and molecular polarizabilities. In addition, to obtain better conformational properties, side chain chi1 and chi2 dihedral parameters were optimized targeting QM data for the respective side chain dipeptide conformations as well as PDB survey data based on the chi1, chi2 sampling from Hamiltonian replica-exchange MD simulations of (Ala)4-X-(Ala)4 in solution, where X is the amino acid of interest. Further improvements include optimizing nonbonded interactions between charged residues to reproduce QM interactions energies of the charged-protein model compounds and experimental osmotic pressures. Validation of the optimized Drude protein FF includes MD simulations of a collection of peptides and proteins including beta-sheet structures, as well as transmembrane ion channels. Results showed that the updated Drude-2019 protein FF yields smaller overall RMS differences of proteins as compared to the additive CHARMM36m and Drude-2013 FFs as well as similar or improved agreement with experimental NMR properties, allowing for long timescale simulation studies of proteins and more complex biomolecular systems in conjunction with the remainder of the Drude polarizable FF.