Molecular Modeling of Endogenous and Exogenous Toxins at Phospholipid Interfaces

Toxic substances constantly inundate the human body. These include potentially harmful drugs and chemicals entering from the external environment, as well as compounds produced internally such as waste products from metabolic processes. Although many drugs and toxins bind to specific proteins embedded in phospholipid layers in the body, the diversity of species having toxic effects indicates that specific binding cannot be the only mechanism by which they act. Therefore, it has been proposed that small molecules may use an indirect method to affect membrane-bound proteins: changing the biomechanical environment so as to effect conformational changes in the protein, thereby compromising its ability to perform its function. If the property changes to the phospholipid layer are sufficiently disruptive, they could also affect the ability of the membrane to function as a barrier against unregulated transport of material. Studies show that small molecules affect the physicochemical properties of phospholipid layers, including changing permeability, fluidity, packing, electrostatic potential, and rheology. The manner in which these changes occur on a molecular level and their possible effects on proteins and other membrane structures is not entirely clear. As such, a molecular-level understanding of alterations they induce in the structure, dynamics and thermodynamics of phospholipid layers may elucidate the mechanisms by which toxins cause adverse effects in the body. Toward this end, we undertook molecular dynamics computer simulations to probe the effects of small, potentially toxic molecules on the biomechanical properties of phospholipid layers in an attempt to clarify the mechanisms through which these molecules associate with and alter the properties of these layers. In this thesis, three different applications of our simulation approach are considered: the mechanisms of differential cytotoxicity of exogenous anticoagulant species, the role played by endogenous metabolites in causing consciousness impairment, and the association of potentially toxic drugs with lipid emulsions acting as detoxification agents. Our simulations reveal the nature of the changes in phospholipid layers and the molecular mechanisms by which these changes occur, as well as the free energies associated with them. Our computational approach provides useful insight and offers predictions that can be tested experimentally.