(764g) Transferable Multiscale Model for Simulating Self-Assembled Skin Lipid Mixtures

The stratum corneum (SC), which is the outermost layer of the epidermis, acts as the primary barrier between the body and environment. The SC is made up of dead corneocyte cells surrounded by a multilamellar matrix of lipid molecules containing over 15 different ceramide classes, cholesterol, and free fatty acids of varying tail lengths. Simplified model systems that contain only a subset of these lipids have been extensively studied as a means of uncovering the role each of the lipids play in the SC. While these experimental studies have led to considerable insight, they are unable to provide an accurate representation of the molecular arrangement of the lipids. Molecular dynamics simulations are a viable means to obtain a 3D representation of these lipid arrangements. While atomistic simulations provide an accurate representation of the molecular-level interactions, they typically begin from preassembled initial structures, for which the final configurations are likely heavily biased by the initial structure due to the low mobility of the lipids. Additionally, atomistic simulations have typically examined bilayer, rather multilayer structures, often due to computational cost, and thus will not accurately capture the structure. Self-assembled structures that start from a randomized initial configuration yield more realistic data as they eliminate this bias, however, the long timescales required for self-assembly and large system sizes needed to study multilamellar structures, necessitates the use of computationally efficient, coarse-grained (CG) rather than atomistic models.

In prior work, CG models and forcefields for ceramide NS [1], cholesterol [in prep], free fatty acids [1], and water have been developed [2] using the multistate iterative Boltzmann inversion (MS-IBI) method. MS-IBI optimizes CG forcefields by considering multiple thermodynamic states simultaneously with the goal of developing a CG forcefield with reduced state dependences and thus increased transferability [3]. Here, we demonstrate the transferability of this CG model and forcefield by examining the behavior of systems containing two additional classes of ceramides: ceramide AP and NP. The underlying CG beads and interaction potentials associated with ceramide AP and NP are taken directly from the ceramide NS forcefield, with no additional MS-IBI optimizations performed; new bond/angle parameters were derived when required. Simulations of self-assembled multilayers containing ceramide AP and NP provide close agreement with corresponding experiments [4]. Thus, these self-assembled structures provide clear insight as to the three dimensional structure of these membranes.

1. Moore, T. C., Iacovella, C. R., Leonhard, A. C., Bunge, A. L. & McCabe, C. Molecular dynamics simulations of stratum corneum lipid mixtures: A multiscale perspective. Biochemical and Biophysical Research Communications. 498, (2018).
2. Moore, T. C., Iacovella, C. R. & McCabe, C. Development of a Coarse-Grained Water Forcefield via Multistate Iterative Boltzmann Inversion. Foundations of Molecular Modeling and Simulation. (2016)
3. Moore, T. C., Iacovella, C. R. & McCabe, C. Derivation of coarse-grained potentials via multistate iterative Boltzmann inversion. J. Chem. Phys. 140, (2014).
4. Schmitt, T., Lange, S., Dobner, B., Sonnenberger, S., Hauß, T., & Neubert, R. H. Investigation of a CER [NP]-and [AP]-Based Stratum Corneum Modeling Membrane System: Using Specifically Deuterated CER Together with a Neutron Diffraction Approach. Langmuir. 34, (2017).