Surfactant surface chemistry and heparin-based anticoagulant drug design studied by molecular dynamics simulation

This dissertation uses molecular dynamics (MD) simulations to mainly focus on the study of the interaction between neutral surfactants-water and anionic surfactant-anionic polyelectrolyte on the water surface. Besides, this study devotes to finding the possible routes of improving the design of a drug candidate, polyethylene-glycol-linked cationic binding groups (PEG)n-HBG, to inhibit polyphosphate (polyP) thrombotic activities. It is found that the behavior of the nonionic polyoxyethylene glycol alkyl ether on the water surface is more anionic-like, even though the surfactant is overall neutral. The non-ionic surfactant increases the depth of the surface anisotropic layer and the average number of hydrogen bonds per water molecule. MD simulation showed that the negatively-charged O atoms have the most impact on the orientation of water as most water molecules arrange with their H atoms pointing toward the surface. In contrast, the behavior of the zwitterionic surfactant, N-dodecyl-N, N-dimethyl-3-ammonio-1-propanesulfonate, on the water surface is more cationic-like as the positively charged group is more capable of orienting interfacial water. The zwitterionic surfactant orients water molecules with their OHs mostly pointing toward the liquid water. While the complex formation between highly-charged surfactants and polyelectrolytes of the same charge is generally expected to be prohibited by the electrostatic repulsion, my study shows it is possible to form thermodynamically stable complexes in the presence of excess ions. With excess Na⁺ ions, the charge screening effect allows anionic polyelectrolyte to weakly interact with anionic surfactant via hydrogen bonds. In the presence of divalent Ca²⁺ ions, the surfactant and the polymer is strongly coupled by forming Ca²⁺ ion bridges and hydrogen bonds. The mechanism of complex formation between (PEG)n-HBG and polyP are studied using metadynamics simulations with the all-atom and coarse-grained force fields. It is shown that the PEG length does not have any impact on the interaction between the (PEG)n-HBG and polyP. However, it mostly improves the drug’s hemocompatibility by preventing the cationic drug from binding to other negatively- charged biomolecules. Increasing the number of the positive charges on the headgroup strengthens drug binding to polyP. It is found that the binding of (PEG)n-HBG remains intact against various lengths of polyP.Applied Science, Faculty ofChemical and Biological Engineering, Department ofGraduat