Modeling of voltage- and ligand-gated ion channels
Abstract
Membrane proteins are critical for signaling and transport, but these processes cannot be accomplished with static structures. To fulfill their functions, channels, transporters, and other proteins undergo transient conformational changes; by their very nature these are quite hard to capture either experimentally or in models. The goal of our research is to explain these processes and how they are regulated both by natural (de-)activation and allosteric modulation. We work with voltage- and ligand-gated ion channels, (i) because of their exceptional importance in the nervous system, and (ii) because we can sample the relevant processes both with simulations (where we lead method development) and electrophysiology experiments.
This application concerns access to high-end computing resources for a large set of applied projects in the Biophysics group at SU & KTH, as well as a number of parallel software development projects. Our work generates a number of high-impact papers both on method development and applications, but we are critically dependent on access to supercomputer resources, primarily at our home base in Sweden.
We specifically seek computing resources for our projects on (A) How Voltage-gated ion channels (VGICs) interact with poly-unsaturated fatty acids, (B) How VGICs are stabilized in the open or closed state by toxins, (C) Simulations of the transitions between open/closed states in Ligand-gated ion channels (LGICs), (D) Simulations of agonist binding and allosteric modulation in the LGIC GluCl, (E) Simulations of models of the human GABAA LGIC, (F) Simulations of P-Type ATPases, (G) Free energy of solvation calculations, and finally (H) method development of the GROMACS molecular dynamics package. While the aggregate application is for a significant amount of resources, it supports a large team, for each subproject of the six subprojects it is in the regime of medium allocations. We do not artificially inflate our needs, but in return we ask SNAC to judge applications individually based on scientific merit, and not reduce them all by a standard fraction. I believe our team provides the research application impact, publication productivity, and software dissemination to justify the resources.
