Exploring the structure of the stratum corneum lipid matrix via molecular dynamics simulations
Moore, Timothy Craig
Skin plays the vital role in human physiology of providing a barrier from the external environment. This barrier function is localized to the lipid matrix of the outermost layer, the stratum corneum. While much has been learned about the molecular origins of the skin barrier, experimental difficulties make a full molecular-level understanding elusive. In this regard, molecular simulation is a useful tool to study the structure of the stratum corneum lipid matrix, as atomic-level resolution is readily available. However, there are challenges in using simulation to study the stratum corneum lipid matrix, owing to the lack of molecular-level details of its organization and the dense, gel-like packing of the individual lipids. While self-assembled structures would help avoid these problems, the computational power required to simulate the self-assembly of atomistically- detailed molecular models is prohibitive. Therefore, less detailed, or coarse-grained, models are required. This dissertation describes work done in developing coarse-grained models of the stratum corneum lipids, and using these models to study their self-assembly. First, a method—multistate iterative Boltzmann inversion (MS IBI)—is developed to address the transferability problem of coarse-grained force fields. The utility of MS IBI is illustrated through its application to several model problems, where it is shown that MS IBI out-performs other methods. Next, MS IBI is applied to develop coarse-grained force fields for water and the lipids of the stratum corneum. The accuracy of the coarse-grained models is evaluated by comparing the structural properties of systems simulated at the atomistic and at the coarse-grained level, where good agreement between the two levels of modeling is found. Finally, the self-assembly of lipids into bilayer and multilayer structures is examined with the coarse-grained model, allowing molecular properties to be measured that are not directly observable with experimental methods. The work described in this dissertation is therefore an important step in using molecular simulation to study the stratum corneum lipid matrix.