Ion channels are ubiquitous proteins--one of Nature?s exquisite nano-scale molecular machines--that reside in membranes of excitable cells. Their role is to convert chemical and electrical stimuli into ionic currents. Conformational changes in the part of the protein responsible for sensing a stimulus (transducer domain) trigger the gate (effector domain), which can open and close, thereby controlling the flux of ions across the cell membrane. Details of this so-called allosteric communication are of broad relevance to physiology: several drug molecules target ion channels, including neurotoxins and anesthetics, and work by interfering with the coupling between the transducer and effector domains. Thus, a molecular-level description of allosteric signal propagation in such voltage-gated-like ion channels will likely inform the design of selective allosteric drugs. Importantly, quantitative allosteric models can be crucial to shed light on the mechanisms of modulation of electrical activity in neurons, an endeavor that is made particularly timely by the recent funding of independent large-scale scientific initiatives (e.g., the US Brain and the EU Human Brain projects), which are aimed at achieving unprecedented understanding of neuronal circuits.
Despite its broad relevance, the macroscopic thermodynamic concept of allostery is difficult to characterize using only experiment. This project aims to use molecular dynamics (MD) based fully atomistic simulations to bridge the gap between thermodynamic observables and the underlying microscopic dynamics involved in the functioning of ion channels. The ultimate goal is to disentangle the intricate circuitry of energetic and statistical coupling among a functioning channel?s constituent amino acids in order to highlight the network of residue-residue interactions sustaining the mechanical coupling between distinct protein domains. To this end, the petascale capabilities of Blue Waters will be harnessed to generate long time-scales MD trajectories. Data generated will involve either the canonical ensemble or, by using enhanced sampling techniques such as metadyamics, appropriately biased probability distributions. Crucial milestones are the characterization of the free-energy landscape for channel activation/opening and its reshaping upon binding of modulating drugs. Knowledge of the free-energy landscape will inform the final milestone of the project, which takes advantage of a novel coarse-grained analysis of the generated MD trajectories to highlight residue-residue interactions crucial for allosteric signal propagation. The study focuses on three families of voltage-gated-like ion channels that are activated by different stimuli: transient receptor potential channels, voltage gated cation channels, and hyperpolarization-activated cyclic nucleotide-binding channels.
