Molecular Simulations and NMR Reveal How Lipid Fluctuations Affect Membrane Mechanics

ABSTRACT Lipid bilayers form the main matrix of functional cell membranes, and their dynamics underlie a host of physical and biological processes. Here we show that elastic membrane properties and collective molecular dynamics are related by the mean-square amplitudes (order parameters) and relaxation rates (correlation times) of lipid acyl chain motions. We performed all-atom molecular dynamics simulations of liquid-crystalline bilayers to further interpret available NMR data. Our analysis entailed development of a theoretical framework that allows direct comparison of carbon-hydrogen (CH) bond relaxations as measured by simulations and NMR experiments. The new formalism enables validation of lipid force fields against NMR data by including a fixed bilayer normal (director axis) and restricted anisotropic motion of the CH bonds described by their segmental order parameters. The simulated spectral density of thermally excited CH bond fluctuations exhibited well-defined spin-lattice (Zeeman) relaxations analogous to those measured by solid-state NMR spectroscopy. Their frequency signature could be fit to a simple power-law function, indicative of collective dynamics of a nematic-like nature. The calculated spin-lattice relaxation rates scaled as the squared order parameters of the lipid acyl chains yielding an apparent bending modulus κ C of the bilayer. Our results show a strong correlation with κ C values obtained from solid-state NMR studies of 1,2-dimyristoyl- sn -glycero-3-phosphocholine (DMPC) bilayers with varying amounts of cholesterol as further validated by neutron spin-echo measurements of membrane elasticity. The simulations uncover a critical role of interleaflet coupling in membrane mechanics and thus provide insights into the molecular sites of emerging elastic properties within lipid bilayers. STATEMENT OF SIGNIFICANCE The lipid make-up of a bilayer determines its measurable properties but how the motions of individual molecules combine to produce these properties remains unclear. By exploiting the synergy between NMR spectroscopy and molecular dynamics (MD) simulations, we show that the lipid dynamics in a bilayer are collective yet segmental in nature and contribute directly to bilayer elasticity. Comparison between MD simulations and NMR entails an improved theoretical framework that allows the two techniques to be directly related. This study thus provides novel insights into the inner workings of lipid membranes while delivering a new tool for validating computational approaches against experimental data.