Multiscale modelling in electrophysiology: from atoms to organs
- Carmen Domene (University of Bath, United Kingdom)
- Simone Furini (Department of Medical Surgery and Bioengineering, University of Siena, Italy)
- Stefano Severi (University of Bologna, Italy)
The flow of electric current through cell membranes plays an essential role in life. All cells have a difference in voltage across the cell membrane, the so-called membrane potential. Some cells, such as neurons and muscle cells use the membrane potential as a signal. Electrophysiology, the study of the electrical properties of biological cells and tissues, involves measurements of electric currents on a wide variety of scales from single ion-channel proteins to whole organs like the heart, and in neuroscience, it includes measurements of the electrical activity of neurons. In these excitable cells, the transport of charged particles through the cell membrane is facilitated by membrane proteins; ion channels and transporters are perhaps the most fundamental interface between cells and their surroundings. Our present day understanding and methods of modeling neural excitability have been significantly influenced by the landmark work of Hodgkin and Huxley. The conceptual idea behind current electrophysiological models is that cell membranes behave like electrical circuits. After decades, the Hodgkin-Huxley model of excitable cells still stands as an outstanding example of how modelling and experiments can complement each other and contribute to the understanding of biological processes. Perhaps, as a result of this early success in the field, electrophysiology is likely to be one of the areas in the life sciences with ample number of examples where experiments, modelling and simulation are connected and form part of the same process e.g. in the description of ion permeation and gating or cardiac modelling [1-4]. Indeed, the field of electrophysiology provides a rich area for modelling and simulation, and has motivated numerous advances in computing and numerical methods [3, 4].
In particular, ion channels play a central role in the regulation of many physiological functions and are now being successfully targeted to treat a large number of diseases. Approximately 13% of known drugs have their primary therapeutic action on ion channels, making them the 2nd largest target class. Worldwide, sales of ion channel drugs account for $12 billion in revenue annually, thus representing a huge area of interest to the biopharma industry. The determination of the crystal structures of several ion channels, as well as advances in cryo-microscopy, NMR and other spectroscopic techniques, have provided insights into their mechanisms of action. With progress in the experimental determination of 3D structures together with the relentless development of computational algorithms, the increasing speed and availability of supercomputers and new hardware technologies, it is now possible to investigate an immense range of biological phenomenon using simulation. More importantly in this area, is to connect and model the interfaces between atomistic, cellular and tissue-level models as current computational models are used to analyze events on different time and length scales in physiology starting from the atomic crystal structures up to organs. Crucially, there is a need to bridge the gaps between molecular, cellular and tissue levels of information to build integrated models as the study of the biological components in isolation is insufficient.
Unfortunately, a major obstacle that hinders progress in this area is the lack of interaction between the communities working at each level. Therefore, in the spirit of the CECAM meetings, the workshop is driven by and responds to the needs of these communities. And as we continue to embrace new technologies and further our theoretical understanding, we will be set to build multiscale models in electrophysiology in the coming years, where governments are heavily investing [see e.g. the Human Brain Project (https://www.humanbrainproject.eu) or the Brain project (http://www.braininitiative.nih.gov)] and where pioneering efforts are also underway to develop neuromorphic computing systems, i.e. systems inspired by the way the human brain works.
In this workshop, we will bring together chemists, physicists, engineers and biologists working in different aspects of ion channels with the aim of establishing links and foster collaboration between basic science researchers and those in bioengineering and medicine. Progress in this area will be realized with the availability of suitable computational techniques, and new developments will be covered.
Four specific areas will be addressed:
 How to optimize algorithms for accelerating state transitions in atomistic simulations of ion channels.
 The potential of mean force along a limited set of reaction coordinates is essential for understanding the evolution of complex system such as ion channels. Having appropriate reaction coordinates is paramount for efficient spatial and temporal sampling. How to estimate these energy maps accurately and efficiently and how to take advantage of this information to link models at different scales will be considered.
 Membrane currents have historically been modelled by Markov models, estimated from experimental data. As much work has been done in the development and use of Markov state models to describe complex processes, we expect a lively discussion on whether and when one needs identifying a single reaction coordinate, or construct Markov models using many metastable states.
 A powerful strategy to model systems on different scales (temporal and spatial) is to use a multiscale approach. Markov models estimated from MD simulations are used to simulate trajectories much longer than the simulations used to compute them. This strategy is used to link the atomic and cellular levels, and will be examined.
The main objectives are:
• Deliver the newest technical approaches, and stimulate further developments as well as future collaborations in experimental and computational methods to simulate the full spatial and temporal information of large numbers of ion channels. Current modelling software does not allow building and simulating multiscale models without having to become involved with the underlying technical details of computational modelling; this key issue will be addressed. In addition, by filling the gaps of modelling efforts at disparate scales, this workshop seeks to identify the molecular and cellular mechanisms that control events, which in turn will lead to the development of novel treatments for several diseases and disorders.
• Identify challenges, priorities and opportunity areas in the multiscale modelling of ion channels. This is expected to trigger appropriate intellectual and joint grant opportunities, and lead to the establishment of novel research directions capable of maximizing the impact of the field in the near future.
• Identify key open questions from experimental ion channel biophysics and the computational biophysics approaches that can be used to address these questions. We anticipate that this discussion between experimentalists and theoreticians will help define successful strategies to address current challenges in ion channel biophysics.
• Promote extensive discussions between experimentalists and theoreticians, between senior and junior scientists, between scientists from academia and the industry. The extensive discussions planned throughout the workshop will help identify priority research questions, promote collaborations, and provide unique opportunities for networking.
• Bring together different approaches to Multiscale modelling in electrophysiology, from atoms to organs. This will help highlight the complexities of working at very diverse scales, promote exchange of ideas between scientists using different approaches, and contribute to the discussion we planned on identifying key open questions and approaches needed to address these questions.
 Mechanism of voltage gating in potassium channels. Jensen MØ, Jogini V, Borhani DW, Leffler AE, Dror RO,Shaw DE. Science 2012, 336(6078), 229-33.
 Molecular dynamics of ion transport through the open conformation of a bacterial voltage-gated sodium channel. Ulmschneider MB, Bagnéris C, McCusker EC, Decaen PG, Delling M, Clapham DE, Ulmschneider JP,Wallace BA. Proc Natl Acad Sci U S A. 2013, 110(16), 6364-9.
 Considerations for the use of cellular electrophysiology models within cardiac tissue simulations.
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 Multi-scale computational modelling in biology and physiology. Southern J, Pitt-Francis J, Whiteley J, Stokeley D, Kobashi H, Nobes R, Kadooka Y, Gavaghan D. Prog iBiophys Mol Biol 2008, 96, 6089.
 A multiscale model linking ion-channel molecular dynamics and electrostatics to the cardiac action potential. Silva JR, Pan H,, Wu D, Nekouzadeh A, Decker KF, Cui J, Baker NA,, Sept D, Rudy Y. Proc Natl Acad Sci U S A. 2009, 106(27), 11102-6.