Nonlinear dynamics of selectivity, conductivity, and gating in biological ion channels
Lead Research Organisation:
University of Warwick
Department Name: Sch of Engineering
Abstract
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Publications
Khovanova N
(2011)
The role of excitations statistic and nonlinearity in energy harvesting from random impulsive excitations
in Applied Physics Letters
Cosseddu S
(2013)
Dynamics of ions in the selectivity filter of the KcsA channel Towards a coupled Brownian particle description
in The European Physical Journal Special Topics
Khovanova NA
(2013)
Characterisation of linear predictability and non-stationarity of subcutaneous glucose profiles.
in Computer methods and programs in biomedicine
Khovanov I
(2013)
Noise-induced escape in an excitable system
in Physical Review E
Tindjong R
(2013)
Self-organized enhancement of conductivity in biological ion channels
in New Journal of Physics
R. Tindjong
(2013)
Non-equilibrium Stochastic Dynamics of Open Ion Channels
in NONLINEAR PHENOMENA IN COMPLEX SYSTEMS An Interdisciplinary Journal
Luchinsky D
(2014)
Observation of "Remote Knock-On", a New Permeation-Enhancement Mechanism in Ion Channels
in Biophysical Journal
Khovanov I
(2014)
Numerical simulations versus theoretical predictions for a non-Gaussian noise induced escape problem in application to full counting statistics
in Physical Review B
Soskin SM
(2015)
Regular rather than chaotic origin of the resonant transport in superlattices.
in Physical review letters
| Description | The project allowed us to make a significant progress in understanding of the key factors regulating activity and properties of the potassium ion channels. During the grant a team has been formed and additional support in the form another EPSRC grant has been secured. This project has helped to identify a number of fundamental problems related to modelling of ion channel and more widely in modelling biological objects. The problems have been formulated and steps to tackle these problems have been performed. This research has been conducted by the Warwick University team in collaboration with Lancaster Nonlinear Dynamics group ands with Bob Eisenberg (Rush University, Chicago). The object of the study was a potassium ion channel KcsA that resembles human K+ channels with respect to the ion permeation and selectivity between potassium and sodium ions. In the central part of the channel, so-called selectivity filter, ions and water molecules move in a single file fashion. The current is regulated by several types of "gates", common to a wide variety of potassium ion channels, which are crucial for physiological functions such as initiation of electrical pulse in excitable cells of the heart. Among these gates, the C-type inactivation involves structural rearrangements in the filter region, and these rearrangements are mostly unknown. The primary activity of our (Warwick) team was aimed to two objectives of the project: (i) Investigate the inactivation mechanism and determinants in the protein sequence and in the coupling between permeation and inactivation revealed by several experimental evidences, (ii) Develop MD simulations of a channel for unambiguously separating all the relevant "slow" variables from the faster motions, so that the former can be represented as a deterministic component and the latter stochastically in terms of Brownian dynamics. Within the first objective the following results have been obtained: Inactivation of potassium KcsA has been described and a mechanism of the inactivation has been proposed. The mechanism was confirmed with calculations performed on different mutants widely reported in the literature as having different inactivation probabilities with respect of the wild type. The central role of the aspartate residue located close the external filter entryway has been demonstrated and a strong coupled network of several residues with the aspartate as a hub has been proved being responsible for the state of the filter. Moreover, the aspartate belongs to the motif TXXTXGYGD that highly conserves among potassium ion channels. It has been found that the location of the ions inside the selectivity filter is one of the key components in the inactivation mechanism. Different residues affecting the filter state are exposed to the extra-cellular bulk. This provides opportunity to control their behaviour and consequently inactivation by binding chemicals, that is to control the inactivation of potassium channels by drugs. The study of the inactivation mechanism has revealed the existence of several configurations of the selectivity filter with different conducting properties. A conductive configuration has been identified. Ion permeation in the conducting configuration identified by this research, was studied and a detailed picture of multi-ions conduction was built in the form of multi-dimensional free-energy surface. Several distinct permeation pathways were identified, and it was shown that these pathways are regulated by diffusion of ion from the intracellular region to the cavity. Once the incoming potassium ion reached the cavity the free-energy gradient promotes the permeation with a barrier-less entering of the ion in the filter. Comparative analysis of sodium and potassium behaviours in the conducting configurations allows us to conclude that a thermodynamically driven selectivity over the two ion species occurs before the entrance of the filter. Additionally it has been shown that a partial knock-on effect can be induced by incoming sodium ions confirming the earlier finding of Lancaster group obtained by using Brownian dynamics model. Sodium's permeation,nevertheless, is unfavoured due to the impossibility of the sodium ion to enter in the filter and finalise the knock-on process. The key result of the second objective is the existence of 1/f component in ion dynamics. The presence of this component is defined by complex re-arrangements of a large number of residues and bonds. It has been shown that widely-used description of an ion in the selectivity filter as a motion of an over-damped particle in multi-stable potential under action of white Gaussian noise(archetypical over-damped Langevin equation) is not valid. Such description should be based on under-damped particle motion, and Generalised Langevin equation with a memory-kernel, which includes 1/f component, has to be used. Additionally, a number of results have been obtained in collaboration with Lancaster group for describing noise-induced transitions in multi-stable systems. These results helped to form a comprehensive picture of ion permeation on Brownian dynamics scale, i. e. considering a flow of ions via the channel. Finally, the project has shown the importance of the presence of an infrastructure for storing and sharing data as well as the necessity of computational resources for data analysis. These components are complementary to high-performance computing facilities used in the course of the project. To develop these components we partially used finance resources initially aimed for travelling. |
| Exploitation Route | Several residues acceptable from extra-cellular environment significantly affect the inactivation. These residues may be controlled by binding chemicals and, consequently, there is an opportunity to control the inactivation of potassium channels by drugs. |
| Sectors | Pharmaceuticals and Medical Biotechnology,Other |
| Description | Responsive Mode |
| Amount | £1,500,000 (GBP) |
| Funding ID | EP/M016889/1 |
| Organisation | Engineering and Physical Sciences Research Council (EPSRC) |
| Sector | Public |
| Country | United Kingdom |
| Start | 04/2015 |
| End | 09/2018 |