Computational studies of natural and synthetic ion channels

This thesis addresses questions pertaining to three different systems-gemini surfactants, synthetic peptide ion channels and M2 proton channel from influenza A virus. The excellent surfactant properties of gemini surfactants enable their applications from consumer products to vectors for gene transfection. The results emerging from a neutron reflection study of a series of these surfactants reveal their unusual interfacial behavior, demanding a higher resolution picture for their further exploration. Synthetic cyclic peptides self-assemble to form excellent ion channels with a wide range of potential applications ranging from nanomaterials to antimicrobial agents, but the mechanism of their self-assembly is not clear. The M2 proton channel was used regularly as a target for anti-influenza drugs before the appearance of resistant viral strains with mutated forms of M2, including the avian flu strain. Although the NMR and X-ray crystal structures reported recently have significantly advanced the understanding of M2, a complete knowledge of the drug binding to the channel required to design new drugs for the mutated forms remains incomplete. The goal of the thesis is to shed light on these uncertainties at the molecular level. Molecular dynamics (MD) simulations at different levels of details have been used as a tool to complement the experiments and answer the unresolved questions. Using atomistic simulations, we observe gemini surfactant aggregation below air-water interface explaining their unusual behavior detected by experiments. Large-scale simulations of coarse-grained (CG) cyclic peptides at a liquid-liquid interface demonstrate a likely self-assembly mechanism and pave the way to the exploration of CG models to study cyclic peptides in different environments and nanomaterials at liquid-liquid interfaces. Atomistic simulations of the transmembrane domain of M2 in DMPC bilayers reveal possible structural transitions that would occur as the channel switches between its open and closed states. The drug binding site and the orientation of the drug in the open state of the channel are confirmed to be in agreement with the one proposed by crystallographic studies, and a change in the drug orientation with the closing of the channel is proposed. In conclusion, the results of MD simulations have filled some missing gaps in the existing pictures that have emerged from experiments and in principle can be used to guide further experiments.