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Register a new userIon Transit Pathways and Gating in ClC Chloride Channels
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ClC chloride channels possess a homodimeric structure in which each monomer contains an independent chloride ion pathway. ClC channel gating is regulated by chloride ion concentration, pH, and voltage. Based on structural and physiological evidence, it has been proposed that a glutamate residue on the extracellular end of the selectivity filter acts as a fast gate. We utilize a new search algorithm which incorporates electrostatic information to explore the ion transit pathways through wild-type and mutant bacterial ClC channels. Examination of the chloride ion permeation pathways supports the proposed important role of the glutamate residue in gating. An external chloride binding site previously postulated in physiological experiments is located near a conserved basic residue adjacent to the gate. In addition, access pathways are found for proton migration to the gate, enabling pH control at hyperpolarized membrane potentials. A chloride ion in the selectivity filter is required for the pH-dependent gating mechanism.
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The finely tuned structures of membrane channels allow selective passage of ions through the available aqueous pores. In order to understand channel function, it is crucial to locate the pore and study its physical and chemical properties. Recently obtained X-ray crystal structures of bacterial chloride channel homologues reveal a complicated topology with curvilinear pores. The commonly used HOLE program encounters difficulties in studying such pores. Here we propose a new pore-searching algorithm (TransPath) which uses the Configurational Bias Monte Carlo (CBMC) method to generate transmembrane trajectories driven by both geometric and electrostatic features. The trajectories are binned into groups determined by a vector distance criterion. From each group, a representative trajectory is selected based on the Rosenbluth weight, and the geometrically optimal path is obtained by simulated annealing. Candidate ion pathways can then be determined by analysis of the radius and potential profiles. The proposed method and its implementation are illustrated using the bacterial KcsA potassium channel as an example. The procedure is then applied to the more complex structures of the bacterial E. coli ClC channel homologues.
We introduce a statistical and linear response theory of selective conduction in biological ion channels with multiple binding sites and possible point mutations. We derive an effective grand-canonical ensemble and generalised Einstein relations for the selectivity filter, assuming strongly coordinated ionic motion, and allowing for ionic Coulomb blockade. The theory agrees well with data from the KcsA K$^+$ channel and a mutant. We show that the Eisenman relations for thermodynamic selectivity follow from the condition for fast conduction and find that maximum conduction requires the binding sites to be nearly identical.
There are many controversial and challenging discussions about quantum effects in microscopic structures in neurons of the human brain. The challenge is mainly because of quick decoherence of quantum states due to hot, wet and noisy environment of the brain which forbids long life coherence for brain processing. Despite these critical discussions, there are only a few number of published papers about numerical aspects of decoherence in neurons. Perhaps the most important issue is offered by Max Tegmark who has calculated decoherence times for the systems of ions and microtubules in neurons of the brain. In fact, Tegmark did not consider ion channels which are responsible for ions displacement through the membrane and are the building blocks of electrical membrane signals in the nervous system. Here, we would like to re-investigate decoherence times for ionic superposition states by using the data obtained via molecular dynamics simulations. Our main approach is according to what Tegmark has used before. In fact, Tegmark didnt consider the ion channel structure and his estimates are only simple approximations. In this paper, we focus on the small nano-scale part of KcsA ion channels which is called selectivity filter and has a key role in the operation of an ion channel. Our results for superposition states of potassium ions indicate that decoherence times are in the order of picoseconds which are 10-100 million times bigger than the order calculated by Tegmark. This decoherence time is still not enough for cognitive processing in the brain, however it can be adequate for quantum states of cooled ions in the filter to leave their quantum traces on the filter and action potentials.
Path-integral ab initio molecular dynamics (PI-AIMD) calculations have been employed to probe the nature of chloride ion solvation in aqueous solution. Nuclear quantum effects (NQEs) are shown to weaken hydrogen bonding between the chloride anion and the solvation shell of water molecules. As a consequence, the disruptive effect of the anion on the solvent water structure is significantly reduced compared to what is found in the absence of NQEs. The chloride hydration structure obtained from PI-AIMD agrees well with information extracted from neutron scattering data. Inparticular, the observed satellite peak in the hydrogen-chloride-hydrogen triple angular distribution serves as a clear signature of NQEs. The present results suggest that NQEs are likely to play acrucial role in determining the structure of saline solutions.
Recently it was demonstrated that long-lived quantum coherence exists during excitation energy transport in photosynthesis. It is a valid question up to which length, time and mass scales quantum coherence may extend, how to one may detect this coherence and what if any role it plays for the dynamics of the system. Here we suggest that the selectivity filter of ion channels may exhibit quantum coherence which might be relevant for the process of ion selectivity and conduction. We show that quantum resonances could provide an alternative approch to ultrafast 2D spectroscopy to probe these quantum coherences. We demonstrate that the emergence of resonances in the conduction of ion channels that are modulated periodicallly by time dependent external electric fields can serve as signitures of quantum coherence in such a system. Assessments of experimental feasibility and specific paths towards the experimental realization of such experiments are presented. We show that this may be probed by direct 2-D spectroscopy or through the emergence of resonances in the conduction of ion channels that are modulated periodically by time dependent external electric fields.
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