Alteration of the Lipid Bilayer Structure by Mg ²⁺

Developing molecular mechanics force fields to model interactions of biological membranes with Mg²⁺ cations is challenging. There are no direct estimates of the binding modes of Mg²⁺ ions with lipid headgroups or other phosphates in the condensed phase. Experimental data on lipid bilayers in Mg²⁺ solution are sparse and limited to biologically relevant but very low ion concentrations. At these concentrations, no statistically discernible effects on bilayer properties are observed. Simulations at these concentrations are difficult due to system size and the extensive conformational sampling required for force field development. Considering these issues, we previously calibrated Mg²⁺-lipid Lennard-Jones cross-terms using benchmarked quantum mechanical target data on small clusters of ions and ligands representative of common cation binding sites on 1-palmitoyl-2- oleoyl-sn-glycero-phosphatidylcholine (POPC). Our simulations with these new Mg²⁺ parameters yielded bilayer structures very similar to those without salt, in agreement with the available experimental data. We adopted this strategy because it worked well for modeling membrane interactions with monovalent cations, for which additional experimental data are available. However, newer studies from our group show that for Mg²⁺ ions, the choice of target Mg²⁺-lipid mimetic clusters is nontrivial. Inclusion of fully coordinated (6-fold) Mg²⁺ ions, which better represent potential ion-lipid structures in the condensed phase, may be critical for selecting models that reproduce experimental condensed-phase interactions of Mg²⁺ with nucleotide phosphates. Using this new protocol, we propose an additional set of Mg²⁺-lipid interaction Lennard-Jones cross-terms. With this parameter set, we find that at concentrations between 100 and 200 mM, there is a systematic thickening of the lipid bilayer, not observed with our previous Mg²⁺-lipid model. Additionally, compared to the earlier model, we observe more Mg²⁺ adsorbed on the bilayer and a larger fraction directly coordinating the lipid headgroups. However, the new model does not alter our previous observation that structural changes in the bilayer correlate with the amount of ionic charge directly coordinating lipid molecules.