New NMRlipids-related publication: Accurate Binding of Sodium and Calcium to a POPC Bilayer by Effective Inclusion of Electronic Polarization

One of the original goals of the NMRlipids project was to find a MD model that correctly describes cation binding to zwitterionic PC lipid bilayers. In the NMRlipids II project, we concluded that the currently available MD models typically overestimate cation binding and that none of them was accurate enough to capture calcium binding details to PC bilayers. Furthermore, the improved ion models available at the time were not sufficient to reproduce the correct binding behavior.

In early 2017, we started to develop a new MD simulation model of POPC in the group of Pavel Jungwirth. The goal was to improve one of the existing lipid force fields to reproduce the experimental Na⁺ and Ca²⁺ ion binding affinities to PC bilayers without destructing the ion-free bilayer properties. We assumed that cation binding could be improved by implicitly including the electronic polarizability to an existing lipid model by using the electronic continuum correction (ECC) [Leontyev et al. PCCP 13, 2613 (2011)]. ECC had been previously applied to ion parameters in Jungwirth's group by simply scaling the ion charges [Kohagen et al. J. Phys. Chem. B 118, 7902 (2014), Kohagen et al. J. Phys. Chem. B 120, 1454 (2016)]; we decided to extend this approach also to lipid models. Our original plan was to proceed using the open collaboration approach, that is, turn our initial development efforts into a NMRlipids project. Due to the surprisingly rapid progress, we, however, decided to finish the manuscript in the traditional way: It is now accepted to be published in the Journal of Physical Chemistry B [J. Melcr, H. Martinez-Seara, R. Nencini, J. Kolafa, P. Jungwirth, and O.H.S. Ollila J. Phys. Chem. B, DOI: 10.1021/acs.jpcb.7b12510]. All our data and files are available in the GitHub repository and in Zenodo (see e.g. DOI: 10.5281/zenodo.1118265), similarly to the NMRlipids projects.

Shortly, we used the Lipid14 parameters of POPC as a starting point and applied ECC to the headgroup and glycerol backbone atoms. The scaling factors of 0.8 and 0.89 were used for partial charges and LJ radii, respectively. Numerical values of the scaling factors were tuned to reproduce the experimentally observed calcium binding affinities as well as structural details without additional ions. Figure 1 shows comparison between the developed ECC-POPC model, Lipid14, and experiments. For more details, further analysis, data, and parameter files see the manuscript in press, the GitHub repository, and Zenodo.

Figure 1: Response of the headgroup order parameters (which is a direct measure for ion binding affinity, see NMRlipids II) to added CaCl₂ in the ECC-POPC model, in the Lipid 14 model, and in experiments.

We are currently running further tests for the developed ECC-POPC model and extending the development to negatively charged phosphatidylserine (PS) lipids. The development of ECC-PS lipids will be done in parallel with the NMRlipids IV project. The GitHub repository for the ECC-PS model development will be publicly available, but at least for now it is separated from the NMRlipids project core.