Despite the vast amount of experimental and theoretical studies on the binding affinity of cations - especially the biologically relevant Na+ and Ca2+ - for phospholipid bilayers, there is no consensus in the literature. Here we show that by interpreting changes in the choline headgroup order parameters according to the 'molecular electrometer' concept [Seelig et al., Biochemistry, 1987, 26, 7535], one can directly compare the ion binding affinities between simulations and experiments. Our findings strongly support the view that in contrast to Ca2+ and other multivalent ions, Na+ and other monovalent ions (except Li+) do not specifically bind to phosphatidylcholine lipid bilayers at sub-molar concentrations. However, the Na+ binding affinity was overestimated by several molecular dynamics simulation models, resulting in artificially positively charged bilayers and exaggerated structural effects in the lipid headgroups. While qualitatively correct headgroup order parameter response was observed with Ca2+ binding in all the tested models, no model had sufficient quantitative accuracy to interpret the Ca2+:lipid stoichiometry or the induced atomistic resolution structural changes. All scientific contributions to this open collaboration work were made publicly, using nmrlipids.blogspot.fi as the main communication platform.

Department of Chemistry Aalto University Espoo Finland

Department of Neuroscience and Biomedical Engineering Aalto University Espoo Finland

Department of Physics Tampere University of Technology Tampere Finland

Department of Physics Tampere University of Technology Tampere Finland and Department of Physics University of Helsinki Helsinki Finland

Fachbereich Physik Freie Universität Berlin Berlin Germany and Max Planck Institute of Colloids and Interfaces Department of Theory and Bio Systems Potsdam Germany

Institut de Biologie et Chimie des Protéines CNRS UMR 5086 Lyon France

Institute of Organic Chemistry and Biochemistry Czech Academy of Sciences Flemingovo nám 2 16610 Prague 6 Czech Republic and Charles University Prague Faculty of Mathematics and Physics Ke Karlovu 3 121 16 Prague 2 Czech Republic

School of Chemistry University of East Anglia Norwich NR4 7TJ UK

Univ Lyon Université Claude Bernard Lyon 1 CNRS Institut Lumiére Matiére F 69622 LYON France

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