Computational prediction of ion permeation characteristics in the glycine receptor modified by photo-sensitive compounds

Abstract

We conduct computational analyses of ion permeation characteristics in a model glycine receptor (GlyR) modified by photo-sensitive compounds. In particular, we consider hypothetical attachment to the channel of charge-neutral chemical groups which can be photo-activated by shining light of an appropriate wavelength on the system. After illumination, the attached molecules become charged via a photodissociation process or excited into a charge-separated state (thus generating a significant electric dipole). We carry out Brownian Dynamics simulations of ion flow through the channel in the presence of the additional charges generated in this fashion. Based on these calculations, we predict that photo-activation of appropriately positioned photo-sensitive compounds near the channel mouth can significantly modify the rate of ion permeation and the current rectification ratio. Possible implications for GlyR-based device designs are briefly discussed.

Soft Wall Ion Channel in Continuum Representation with Application to Modeling Ion Currents in α-Hemolysin

“…Other existing methods of ion current prediction sacrifice the atomistic representation of a system in favor of computational efficiency. These methods include Brownian dynamics (BD),7–10 dynamic lattice Monte Carlo (DLMC)11,12 and Poisson-Nernst-Planck (PNP) theory 9,13–18. All three approaches share a number of common approximations, e.g .…”

“…Other existing methods of ion current prediction sacrifice the atomistic representation of a system in favor of computational efficiency. These methods include Brownian dynamics (BD), − dynamic lattice Monte Carlo (DLMC), , and Poisson−Nernst−Planck (PNP) theory. ,− All three approaches share a number of common approximations, for example, a solvent and a membrane are treated implicitly, while the protein may be represented in atomistic detail (albeit most often as a rigid body). The main difference between these coarse-grained methods of modeling is in the representation of the mobile ions.…”

“…Both BD and PMFPNP methods also depend on the choice of an ion diffusion coefficient, which, in general, is an inhomogeneous function in space. Although diffusion coefficients of ions exhibit complicated forms in the vicinity of proteins, most recent reports on modeling channel conductance neglect the fine three-dimensional dependence of the diffusion coefficient on an ion position in the channel and assign either a single constant value of the diffusion constant for the whole pore, ,, or a few constant values for distinct pore regions . Recently we have tested several accurate approaches for the estimation of diffusion coefficients in channels .…”

Enhanced Sampling of Nonequilibrium Steady States

“…Given that several cell-surface receptors and cytoskeletal components appear to be shear sensitive (85,86), we anticipate that these studies will be just the start of characterizing biomolecular conformational change in flow. The enhanced sampling methods should also enable studies of ion channels under strong electromotive forces, to examine in particular whether coupling between the ions and the protein at high fields contributes to rectification (asymmetric conductance) (87,88).…”