Molecular Modeling of Lipid Aggregates: Theory and Application

The ability of cell membranes to perform a wide variety of biological functions stems from the organization and composition of its molecular constituents. There are many engineering applications, such as liposome drug delivery carriers, whose functionality takes advantage of the structure to function relationship of lipid membranes. The fundamental understanding of the relationship between the thermodynamic behavior and structure of lipid membranes and the molecular properties of their lipid constituents is crucial to the successful design of lipid related applications. However, information about how the local microscopic composition of lipid membranes responds to the presence of proteins and nanomaterials is challenging given the intrinsic experimental and theoretical difficulties of studying such small-scale systems.;The present work generalizes a self consistent mean field theory for the study of the thermodynamic and structural behavior of lipid bilayers as a function of its molecular composition and physicochemical environments. This novel molecular theory provides with the ability of performing systematic thermodynamic calculations at relatively low computational costs while considering a detailed molecular description of the system under study. The competition of all relevant molecular interactions, such as electrostatics, vdW and chemical equilibria, in the membrane system is described. The developed molecular theory is applied to study how the protonation state of pH-sensitive amphiphiles in a membrane system affects the membrane's morphology. The molecular theory results demonstrate that the protonation state of ionizable groups within amphiphilic membranes shows a highly complex non-monotonic dependence on bulk salt concentration and pH strength. This result suggests that information about the pKa of the molecules is not sufficient to predict the protonation state of the ionizable groups in the membrane system. The molecular theory is also applied to study how the presence of proteins or functionalized nanoparticles near a multicomponent membrane surface leads to changes in its local membrane composition. The results support an electrostatic dependent recruitment mechanism of oncogenic RhoA proteins to the cell membrane. Finally, the molecular theory results describe how nanoparticle functionality and/or membrane molecular composition can be tuned to enhance or suppress nanoparticle adsorption on to phospholipid membranes.