Ions In Action - Studying Ion Channels By Computational Electrophysiology In Gromacs

Ion channels play a fundamental role in maintaining vital electrochemical gradients across the cell membrane and in enabling electrical signaling in cells. Understanding their functional mechanism is crucial for facilitating drug design on this important class of membrane proteins. Key characteristics of ion channel function that are commonly quantified experimentally are ionic permeation rates and selectivities. The Computational Electrophysiology (CompEL) protocol allows the investigation of ion channels in GROMACS all-atom molecular dynamics simulations. By employing an ion/water exchange protocol in a double-membrane simulation setup, a steady state with a continuous flow of ions through the channels is achieved. The recorded ion permeation events directly reveal conductance, selectivity, and rectification behavior, which all allow a straightforward comparison to experimental quantities. In addition, the ionic pathways through the channels are readily revealed. CompEL is available in GROMACS and has a negligible impact on the simulation performance even in parallel.Recent application to the bacterial channel PorB resulted in conductance and selectivity values and revealed the pathways of traversing ions. For a mutant, pathway disruption was observed, thereby explaining its resistance to certain antibiotics. The conductance calculated from the simulations agreed very well with measured conductances. Other successful examples of CompEL include the discovery of an unexpected ionic pathway in the anti-microbial peptide dermcidin as well as the identification of a novel conduction mechanism in the potassium channel KcsA. We finally investigated the conductance and the gating mechanism of pentameric ligand-gated ion channels such as GLIC. We constructed a reaction coordinate from two crystal structures, which have been proposed to represent the open and closed states of the channel, respectively. Constraining the pore to specific positions on that reaction coordinate allowed us to sample the conductivity at these positions. CompEL confirms that the assumedly open structure is indeed conducting and cation-selective (with conductances in the pS range, comparable to published experimental values), whereas the closed structure is indeed non-conducting. Moreover, conductance values steadily increase along the closed-to-open transition and are correlated with the amount of water in the pore.