Interactions of Water and Alkanes: Modifying Additive Force Fields to Account for Polarization Effects.

Atomistic biomolecular simulations predominantly utilize additive force fields (FF), where the electrostatic potential is modeled by fixed point charges. Among other consequences, the lack of polarizability in these models undermines the balance of hydrophilic/hydrophobic nonbonded interactions. Simulations of water/alkane systems using the TIP3P water model and CHARMM36 parameters reveal a 1 kcal/mol overestimate of the experimental transfer free energy of water to hexadecane; more recent optimized water models (SPC/E, TIP4P/2005, TIP4P-Ew, TIP3P-FB, TIP4P-FB, OPC, TIP4P-D) overestimate this transfer free energy by approximately 2 kcal/mol. In contrast, the polarizable SWM4-NDP and SWM6 water models reproduce experimental values to within statistical error. As an alternative to explicitly modeling polarizability, this paper develops an efficient automated workflow to optimize pair-specific Lennard-Jones parameters within an additive FF. Water/hexadecane is used as a prototype and the free energy of water transfer to hexadecane as a target. The optimized model yields quantitative agreement with the experimental transfer free energy and improves the water/hexadecane interfacial tension by 6%. Simulations of five different lipid bilayers show a strong increase of water permeabilities compared to the unmodified CHARMM36 lipid FF which consistently improves match with experiment: the order-of-magnitude underestimate for monounsaturated bilayers is rectified and the factor of 2.8-4 underestimate for saturated bilayers is turned into a factor of 1.5-3 overestimate. While agreement with experiment is decreased for the diffusion constant of water in hexadecane, alkane transfer free energies, and the bilayers' area per lipid, the method provides a permeant-specific route to achieve a wide range of heterogeneous observables via rapidly optimized pairwise parameters.