Abstract
Kinetic models of ion channels: from atomic structures to membrane currents Ion channels are transmembrane proteins that regulate the movement of ions across cell membranes. The ion channels-mediated currents are involved in a plethora of biological processes, including cardiac contraction, nerve transmission, and cell homeostasis. Mutations of channels, or their interactions with pharmaceutical molecules, can modify these ion fluxes, with important consequences in numerous diseases, with cardiac arrhythmias and cystic fibrosis being two relevant examples. Thus, there is a great interest in numerical techniques for simulating the activity of ion channels. Nowadays, there are two approaches that are commonly used to model ion channels. The functional properties are usually described by Markov Models (MMs) estimated from experimental data. These MMs reproduce quantitatively the membrane currents, but they do not reveal how channels operate at the atomic level. Conversely, Molecular Dynamics (MD) simulations reproduce the behaviours of proteins at atomic level, but because of the high computational cost, they cannot be routinely used to simulate membrane currents. The aim of this project is to fill the gap between empirical models of membrane currents and atomic simulations of ion channels. Thanks to recent theoretical and computational advancements, it is now possible to estimate MMs directly from MD simulations. Inspired by this possibility, we designed a multiscale algorithm for simulating ion channels. MD simulations will be used to sample the dynamics of channels at atomic scale under different boundary conditions. Then, these atomic trajectories will be used to estimate kinetic models that describe the processes under investigation (e.g. ion conduction and inactivation) by a minimal number of long-lived metastable states and the corresponding transition rates. Thanks to this approach, it will be possible to include atomic details in kinetic simulations that can be directly compared with experimental data on membrane currents. The methods will be tested in two potassium selective channels: KcsA and hERG. KcsA is the prototypical system in the field of atomic simulations of ion channels, and consequently it is an ideal model for testing novel methods. hERG is a crucial channel for the electrical activity of cardiac cells. Electrophysiological experiments of hERG will be performed and compared with kinetic models estimated from MD simulations. The aim of this comparison is to identify the atomic mechanisms responsible for the functional properties of hERG, in particular its peculiar C-type inactivation properties, with important implications for the current understanding of the role of hERG mutations in cardiac arrythmias and for drug-design. More than 20 years after the publication of the first atomic structure of a potassium channel, many questions regarding the mechanisms responsible for the functioning of these proteins are still unanswered. The combination of atomic simulations and experimentally-derived kinetic models developed in this project could contribute to their understanding. In particular, we anticipate that our simulation tools will reveal how the boundary conditions (membrane potentials and ion concentrations) modify the mechanisms of conduction/selectivity, and if these mechanisms differ among K+-channels. Computational models that relate atomic structures to membrane-currents will be useful for predicting the effects of residue mutations, eventually providing a guide to better understand pathogenic mutations, and for the design of ion channels with desired functional characteristics. With respect to C-type inactivation, we will contribute to the current debate on the relation between atomic structures and functional states. In detail, with the combination of simulations and experiments, we anticipate to identify candidate atomic structures for the Na+-conductive state of hERG. Since this Na+-conductiv
Project details
Unibo Team Leader: Simone Furini
Unibo involved Department/s:
Dipartimento di Ingegneria dell'Energia Elettrica e dell'Informazione "Guglielmo Marconi"
Total Eu Contribution: Euro (EUR) 197.866,00
Total Unibo Contribution: Euro (EUR) 97.806,00
Project Duration in months: 24
Start Date:
28/09/2023
End Date:
28/02/2026
