The recent determination of several crystal structures of voltage-gated ion channels has catalyzed computational efforts of studying these remarkable molecular machines that are able to conduct ions across biological membranes at extremely high rates without compromising the ion selectivity.

Starting from the open crystal structures, we have studied the gating mechanism of these channels by molecular modeling techniques. Firstly, by applying a membrane potential, initial stages of the closing of the channel were captured, manifested in a secondary-structure change in the voltage-sensor. In a follow-up study, we found that the energetic cost of translocating this 3₁₀-helix conformation was significantly lower than in the original conformation. Thirdly, collaborators of ours identified new molecular constraints for different states along the gating pathway. We used those to build new protein models that were evaluated by simulations. All these results point to a gating mechanism where the S4 helix undergoes a secondary structure transformation during gating.

These simulations also provide information about how the protein interacts with the surrounding membrane. In particular, we found that lipid molecules close to the protein diffuse together with it, forming a large dynamic lipid-protein cluster. This has important consequences for the understanding of protein-membrane interactions and for the theories of lateral diffusion of membrane proteins.

Further, simulations of the simple ion channel antiamoebin were performed where different molecular models of the channel were evaluated by calculating ion conduction rates, which were compared to experimentally measured values. One of the models had a conductance consistent with the experimental data and was proposed to represent the biological active state of the channel.

Finally, the underlying methods for simulating molecular systems were probed by implementing the CHARMM force field into the GROMACS simulation package. The implementation was verified and specific GROMACS-features were combined with CHARMM and evaluated on long timescales. The CHARMM interaction potential was found to sample relevant protein conformations indifferently of the model of solvent used.