(561h) Multiscale Modeling of the Structure and Permeability of Self-Assembled Stratum Corneum Lipid Membranes

The barrier function of human skin is known to be localized to the stratum corneum (SC), which is composed of corneocytes surrounded by a dense, lamellar lipid matrix composed of ceramides, cholesterol and free fatty acid of various lengths. Simplified model systems that contain only a subset of these lipids are commonly studied via both experiment and simulation, with the goal of uncovering the role that each of the lipids play in the structure of the lipid matrix and barrier properties of the SC. However, modeling such systems can be challenging. Atomistic models, while accurate, incur a high computational cost and, because lipids have limited mobility, results may be unduly influenced by the starting lipid configuration [1]. Computationally efficient coarse-grained (CG) models allow simulation of large system sizes and long timescales require to self-assemble lipids into multi-layer membranes that are representative of experiment [2,3,4]. However, by their construction, information is lost in CG models, which makes examination of structure, molecular interactions, and transport properties less reliable than from atomistic models.

To examine the structure and properties of SC lipid mixtures, we employ a multiscale modeling approach that enables efficient atomistic examination of self-assembled multi-layer SC lipid membranes [4]. Here, atomistic simulations are used to parameterize CG models via the multi-state iterative Boltzmann inversion (MS-IBI) method [3]. In the MS-IBI method, optimizations are performed simultaneously over a range of target thermodynamic and structural statepoints, as well as using different ensembles to ensure appropriate relationships are captured (e.g., density-pressure relationships), resulting in CG force fields with a high degree of transferability between different lipids and states. The MS-IBI derived CG force fields are used to perform self-assembly of membranes composed of the SC lipids [2,4,5], including large multi-layer systems. The self-assembled structures from the CG simulation are then used to construct more realistic pre-assembled atomistic configurations. In this approach, the self-assembled lamellae define the initial atomistic morphology (e.g., in-plane arrangement of lipid components) and ceramide conformations (e.g., hairpin or extended configurations of each molecule) in each layer. Atomistic simulations of these initial configurations then uses standard relaxation procedures to obtain atomistically detailed configurations that should be more representative of experiment. Here, we utilize this multiscale approach to provide detailed examination of the self-assembly, lipid morphology, lipid-tail ordering, hydrogen bonding, free energy profiles, and diffusion coefficients for different lipid mixtures, in order to establish relationships between composition and permeability of multi-layer SC lipid membranes.

[1] Moore T.C., Hartkamp R., Iacovella C.R., Bunge A.L., McCabe C. The Influence of Ceramide Tail Length on the Structure of Bilayers Composed of Stratum Corneum Lipids, Biophysical Journal, 2018 114, 113-125

[2] Moore T. C., Iacovella, C. R., Hartkamp, R., Bunge, A. L. & McCabe, C. A Coarse-Grained Model of Stratum Corneum Lipids: Free Fatty Acids and Ceramide NS. J. Phys. Chem. B 2016 120, 9944–9958

[3] Moore T. C., Iacovella, C. R. & McCabe, C. Derivation of coarse-grained potentials via multistate iterative Boltzmann inversion. J. Chem. Phys. 2014, 140, 224104

[4] Shamaprasad P, Moore T.C. Xia, D., Iacovella C.R., Bunge A.L., McCabe C., Multiscale simulation of ternary stratum corneum lipid mixtures: Effects of cholesterol composition, under-review

[5] Moore T.C., Iacovella C.R., Leonhard A., Bunge A.L., McCabe C., Molecular Dynamics Simulations of Stratum Corneum Lipid Mixtures: A Multiscale Perspective, Biochemical and Biophysical Research Communications, 2018 498, 313-318