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Molecular dynamics (MD) force fields for lipids and ions are typically developed independently of one another. In simulations consisting of both lipids and ions, lipid-ion interaction energies are estimated using a predefined set of mixing rules for Lennard-Jones (LJ) interactions. This, however, does not guarantee their reliability. In fact, compared to the quantum mechanical reference data, Lorentz-Berthelot mixing rules substantially underestimate binding energies of Na(+) ions with small molecule analogues of lipid headgroups, yielding errors on the order of 80 and 130 kJ/mol, respectively for methyl acetate and diethyl phosphate. Previously, errors associated with mixing force fields have been reduced using approaches like ‘NB-fix’ in which LJ interactions are computed using explicit cross terms rather than those from mixing rules. Building on this idea, we derive explicit lipid-ion cross terms that also may implicitly include many-body cooperativity effects. Additionally, to account for interdependency between cross terms, we optimize all cross terms simultaneously by performing high-dimensional searches using our ParOpt software. The cross terms we obtain reduce the errors due to mixing rules to below 10 kJ/mol. MD simulation of lipid bilayer conducted using these optimized cross terms resolve the structural discrepancies between our previous simulations and small-angle X-ray and neutron scattering experiments. These results demonstrate that simulations of lipid bilayers with ions that are accurate up to structural data from scattering experiments can be performed without explicit polarization terms. However, it is worth noting that such NB-fix cross terms are not based on any physical principle; a polarizable lipid model would be more realistic, and is still desired. Our approach is generic and can be applied to improve accuracies of simulations employing mixed force fields.

Recent advances in nanotechnology bring to the forefront a new class of extrinsic constraints for remodeling lipid bilayers. In this next-generation technology, membranes are supported over nanoporous substrates. The nanometer-sized pores in the substrate are too small for bilayers to follow the substrate topology; consequently, the bilayers hang over the pores. Experiments demonstrate that nanoporous substrates remodel lipid bilayers differently from continuous substrates. The underlying molecular mechanisms, however, remain largely undetermined. Here we use molecular dynamics (MD) simulations to probe the effects of silica-type hydroxylation and charge densities on adsorbed palmitoyl-oleoylphosphatidylcholine (POPC) bilayers. We find that a 50% porous substrate decorated with a surface density of 4.6 hydroxyls/nm(2) adsorbs a POPC bilayer at a distance of 4.5 Å, a result consistent with neutron reflectivity experiments conducted on topologically similar silica constructs under highly acidic conditions. Although such an adsorption distance suggests that the interaction between the bilayer and the substrate will be buffered by water molecules, we find that the substrate does interact directly with the bilayer. The substrate modifies several properties of the bilayer-it dampens transverse lipid fluctuations, reduces lipid diffusion rates, and modifies transverse charge densities significantly. Additionally, it affects lipid properties differently in the two leaflets. Compared to substrates functionalized with sparser surface hydroxylation densities, this substrate adheres to bilayers at smaller distances and also remodels POPC more extensively, suggesting a direct correspondence between substrate hydrophilicity and membrane properties. A partial deprotonation of surface hydroxyls, as expected of a silica substrate under mildly acidic conditions, however, produces an inverse effect: it increases the substrate-bilayer distance, which we attribute to the formation of an electric double layer over the negatively charged substrate, and restores, at least partially, leaflet asymmetry and headgroup orientations. Overall, this study highlights the intrinsic complexity of lipid-substrate interactions and suggests the prospect of making two surface attributes-dipole densities and charge densities-work antagonistically toward remodeling lipid bilayer properties.