The experimental and computational study of solid state nanopores as synthetic counterpart of biological ion channels has been a major research topic in nanofluidics and biotechnology in the last decade. Ideally, such biomimetic devices should be designed to have the desired properties in terms of selectivity and gating. Selectivity refers to the difference in terms of flux of different ionic species under the same chemical potential difference, while gating refers to the mechanism of transition between open (conductive) and closed (nonconductive) configurations. Hydrophobic gating has recently emerged as a gating mechanism found in several biological channels. The mechanism of hydrophobic gating is related to the reversible formation of a vapour bubble inside hydrophobic nanopores due to the extreme water confinement, resulting in stochastic transitions between a dry and a wet state. Since ions can only go through the pore in the wet state, controlling the wet and dry transitions with voltage or hydrostatic pressure tunes the channel conductance. There is considerable interest in understanding hydrophobic gating in biology and in the design of synthetic gated channels. However, a clear understanding of the dynamics of the hydrophobic gate in response to external stimuli and the dependence of such dynamics on the microscopic features of the pore is still to be achieved. Here, a coarse graining approach is proposed to extract the long time behaviour of the pore from an atomistic model of hydrophobic nanopore. Restrained molecular dynamics simulations will be used to extract the free energy and diffusivity as a function of two coarse grained variables: the pore filling and the axial position of a tagged ion. The outcome of these simulations will be used to perform Langevin simulations to extract the rates of ion crossing and of pore wetting and drying, which are out of the range of Molecular Dynamics simulations due to their computational cost.
The design of synthetic nanopores which allow selective, nonlinear and gated transport of ions to mimic the functioning of biological ion channels has attracted considerable interest from a heterogeneous community of scientists at the boundary between biotechnology, engineering, chemistry and condensed matter physics [1,2,3]. Recent developments have shown great promise for the control of selectivity [4] and of the current-voltage relations [5] as a function of pore geometry, charge, surface functionalization and of the ionic solution. For what concerns the gating, it has been shown that introducing an electrode in the membrane allows a considerable control of the ionic transport across nanoporous membranes [6]. Different types of systems capable of gating have been studied, ranging from pH responsive membranes [7] to biological gating based on protein binding to DNA pores [8]. Hydrophobic gating is considered to be an attractive mechanism since it appears naturally in all the nanopores which meet the requirements in terms of geometry and hydrophobicity [9], and it doesn't rely on specific surface functionalizations or on biological macromolecules whose stability is extremely sensitive to temperature changes. However, a complete physical understanding of the dynamics of hydrophobic gating which would be required for the design of biomimetic devices is still lacking [10]. On the other hand, lumped element models of ion channels have been extensively explored and used in computational neurosciences and in neural networks. Such lumped elements are always extracted from the macroscopic behaviour of the channel, or calibrated in order to obtain a desired response in terms of electrical current to a given voltage stimulus, and hence cannot be related to the microscopic physical details of the channel.
The outcomes of the proposed research will improve the fundamental knowledge of the hydrophobic gating mechanism, providing design principles for a novel class of devices with specific features in terms of macroscopic observables: conductance, selectivity, response to voltage and pressure stimuli. In addition, the project is expected to provide insights into the mechanism of hydrophobic gating in biological systems by providing a fingerprint of the features of hydrophobic gating (e.g. current-voltage relation) as opposed to other biological gating mechanisms. From the methodological point of view, the proposed coarse graining process can be applied to the study of different systems and gating mechanisms (e.g. voltage-dependent or mechanosensitive biological channels). This contribution will be highly valuable since the long-time macroscopic behaviour of the ion channels is closely related to their microscopic structure. This is a multiscale problem which requires a coarse graining of the system in order to allow a quantitative approach required for the design of new devices.
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