Dr. Timothy Moore gives a seminar on Coarse-Graining

Abstract:

The barrier function of human skin is localized to its outermost layer, the stratum corneum (SC); specifically, the lipid matrix which surrounds dead, flat corneocytes is thought to be the main barrier to chemical penetration through the skin. The chemical makeup of the SC lipids is known, but the molecular level details of its structure are not, in part due to the fact that 14 unique lipids have been identified in the SC. As such, experiments often consider simplified mixtures of synthetic lipids whose composition can be precisely controlled, however, even simple systems lead to different hypotheses (e.g., whether two-tailed ceramide lipids adopt a hairpin or extended conformation in lamellar structures). Molecular simulation is an important complement to these experimental studies, as simulation provides a direct 3-D molecular-level resolution and precise control over composition. Thus far, most simulation studies of SC lipids
have focused on pre-assembled structures. While such studies have offered much insight into lipid-lipid and lipid-water interactions, it is possible that the preassembled structures are not representative of the molecular structures in the skin, given the low diffusion coefficient of the lipids and the fact that single bilayers are considered, rather than experimentally/biologically relevant multilayer structures. As such, self-assembled structures would provide a more realistic structure of SC lipid systems, but the timescales required to access self-assembly, and the system sizes needed to model multilayer structures, are likely prohibitive for atomistic-detail models, necessitating the use of coarse-grained (CG) models.
In this talk, I will show how standard coarse-graining algorithms yield force fields that lack state point transferability, which is troublesome for studying self-assembly because of its inherent multistate nature. I will then present a solution to the transferability problem: multistate iterative Boltzmann inversion (MS IBI). The crux of MS IBI is that many different CG force fields may accurately represent a given system at different state points, and the optimal model is the one with the best representability across different state points. I will illustrate the use of MS IBI for several model systems, and then apply it to develop CG models for the lipids of the SC. Finally, I will present the self-assembly of multilamellar structures present in the SC, and reveal the intramolecular conformations of ceramides within the structure. These self-assembled structures therefore provide clear insight into the experimentally proposed molecular models of lipid organization in the SC, which is enabled by the development of accurate CG force fields via MS IBI.