The development of a coarse-grain biomembrane model and its use in multiscale simulations of solute permeability

Abstract

A new simplified particle-based computer model for hydrated phospholipid bilayers is pre- sented. In the model, each lipid molecule, in reality comprising more than one hundred atoms, is reduced to a collection of ten "coarse-grain" macrounits. Compared with available coarse-grain methods, three novel aspects are introduced. First, electrostatics are explicitly incorporated via charges and dipoles. Second, water is accurately (yet efficiently) described, on an individual level, by the soft sticky dipole model. Third, hydrocarbon tails are modelled using the anisotropic Gay-Berne potential. Simulations are conducted by rigid body molec- ular dynamics, using software specifically designed and implemented for this project. The technique developed proves two orders of magnitude less demanding of computational re- sources than traditional atomic-level methodology. The model is parameterised to reproduce the experimental area and volume per lipid, order parameters, and the self-assembly process. Self-assembled bilayers quantitatively reproduce experimental observables such as electron density, compressibility moduli, dipole potential, lipid diffusion and water permeability. The lateral pressure profile is calculated, along with the elastic curvature constants of the Helfrich expression for the membrane bending energy: results are consistent with experimental esti- mates and atomic-level simulation data. Several of the results presented are obtained for the first time using a coarse-grain method. The model is also directly compatible with atomic- level force-fields, allowing mixed systems to be simulated in a multiscale fashion. Efficient multiscale simulations are conducted to predict the permeability coefficient of a number of atomic-level solutes, including small organic molecules, large drugs and steroid hormones. Results prove broadly consistent with previous atomic-level calculations and available ex- perimental data. In particular, despite discrepancies in the absolute magnitudes, the solute relative permeability coefficients, and hence the permeability ranking orders, are consistently reproduced.

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