(382g) Multiscale Modeling of 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 at least 14 unique ceramides, along with 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 each of the lipids play in the structure and properties of the SC. While atomistic simulations provide an accurate representation of the molecular-level interactions of the SC lipids, such simulations are typically performed starting from pre-assembled structures; in such cases, the final configurations are likely heavily biased by the initial, assumed structures due to the low mobility of the lipids [1]. Furthermore, such simulations typically assume bilayer configurations for computational efficiency; bilayer simulations, while instructive, will not fully capture the structure of the experimentally relevant multilayered systems. In particular, they do not allow for the two-tailed ceramide lipids to adopt linear, extended conformations that span multiple leaflets, as has been proposed from experiment, and they also do not capture lipid head-head interfaces[2]. Self-assembled structures that start from isotropic mixtures eliminate the bias associated with assuming a structure. However, the long timescales required for self-assembly and large system sizes needed to study multilamellar structures, makes performing self-assembly using atomistic models infeasible at the current time. Computationally efficient, coarse-grained (CG) models can be used to access these longer timescales and larger systems sizes required [3]. However, CG models, by the nature of their construction, do not possess the same level of detail of atomistic systems, which may limit their ability to accurately model the structure and associations in lipid membranes. As such, to reliably study the SC with simulation, an approach that combines the benefits of both atomistic and CG models is required.

To address these issues, we employ a multiscale approach to modeling the SC lipids. Atomistic simulations are used to parameterize CG models via the multi-state iterative Boltzmann inversion (MS-IBI) method [3]. The MS-IBI method performs optimizations 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. The CG force fields derived via MS-IBI are used to perform self-assembly of large multilamellar membranes composed of the SC lipids[2,4,5]. The structures predicted by the CG self-assembly process are used to construct more realistic pre-assembled multilayer atomistic configurations. In this approach, the morphology of the lipids (e.g., in-plane arrangement of lipids) and their conformations (e.g., which ceramides are hairpin and which are extended) are defined by the CG configuration. The resulting atomistic initial configurations are then simulated using standard procedures to arrive at more realistic atomistic multilayer configurations. Comparisons of these simulations to experimental neutron scattering data show close agreement and provide a more detailed understanding of the 3d structure of the SC lipid membranes [5].

[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] 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

[5] Moore, T.C. Shamaprasad P, Iacovella C.R., Bunge A.L., McCabe C., Multiscale Simulations of Stratum Corneum Lipid Mixtures, in preparation