Solvent-mediated forces in protein dielectrophoresis

DEP is an established method to manipulate micrometer-sized particles, but standard continuum theories predict only negligible effects for nanometer-sized proteins despite contrary experimental evidence. A theoretical description of protein DEP needs to consider details on the molecular scale. Previous work toward this goal addressed the role of orientational polarization of static protein dipole moments for dielectrophoretic effects, which successfully predicts the general magnitude of dielectrophoretic forces on proteins but does not readily explain negative DEP forces observed for proteins in some experiments. However, contributions to the protein chemical potential due to protein-water interactions have not yet been considered in this context. Here, we utilize atomistic molecular dynamics simulations to evaluate polarization-induced changes in the protein solvation free energy, which result in a solvent-mediated contribution to dielectrophoretic forces. We quantify solvent-mediated dielectrophoretic forces for two proteins and a small peptide in water, which follow expectations for protein-water dipole-dipole interactions. The magnitude of solvent-mediated dielectrophoretic forces exceeds predictions of nonmolecular continuum theories, but plays a minor role for the total dielectrophoretic force for the simulated proteins due to dominant contributions from the orientational polarization of their static protein dipoles. However, we extrapolate that solvent-mediated contributions to negative protein DEP forces will become increasingly relevant for multidomain proteins, complexes and aggregates with large protein-water interfaces, as well as for high electric field frequencies, which provides a potential mechanism for corresponding experimental observations of negative protein DEP.