Computational design of biomimetic nanopores: a molecular dynamics study

Molecular dynamics simulations are used to study the function of hydrophobic gates within models of biomimetic nanopores and in ligand-gated ion channels. A computational approach to building and simulating model β-barrel nanopores has been established to explore the effects of changing the shape and polarity of amino acids lining the pore lumen. Changing the position of such residues resulted in different water conductive states. In 14 β-strand pores, a computationally transplanted hydrophobic barrier to water and ions has been demonstrated and characterised in detail using free energy calculations. Electrowetting of such a hydrophobic gate within a model β-barrel nanopore is demonstrated in simulation, using two different methods to apply a transmembrane electric eld. An increase in the transmembrane voltage results in breakdown of the hydrophobic barrier, resulting in the ow of water and ions. The effect (electrowetting) is shown to be reversed upon the removal of the transmembrane voltage. An investigation into the possible hydrophobic gate of the 5-HT3 receptor channel via free energy calculations and simulations con firmed that the crystal structure is in a closed conformation with respect to the ow of ions. This demonstrates that simulations and free energy calculations may be used to functionally annotate crystal structures of ion channels.