Access resistance in protein nanopores. A structure-based computational approach

Single-channel conductance measurements in biological pores have demonstrated the importance of interfacial effects in nanopores, particularly in protein channels with low aspect ratio (length over aperture radius). Access resistance (AR), the contribution to the total measured resistance arising from the electrodiffusive limitation that ions experience in passing from bulk solution to confinement within the pore, becomes essential in the description of ionic transport across these biological channels. Common analytical estimates of AR are based on idealized nanopore models, cylindrical in shape, electrically neutral and embedded in a neutral substrate. Here we calculate the AR of five protein channels by using their atomic structure and a mean-field approach based on solving 3D Poisson and Nernst-Planck equations. Our approach accounts for the influence of the protein charged ionizable residues, the geometry of the pore mouth and the ion concentration gradients near the pore. We compare numerical calculations with the few available AR measurements and show for several protein channels that analytical predictions tend to overestimate AR for physiological concentrations and below. We also discuss the relationship between AR and the size of the channel aperture in single-pore channels and three-pore channels and demonstrate that in the latter case, there is an enhancement of AR

PEG Equilibrium Partitioning in the α-Hemolysin Channel: Neutral Polymer Interaction with Channel Charges

We study the interaction of neutral polyethylene glycol (PEG) molecules of different molecular weights (MWs) with the charged residues of the α-hemolysin channel secreted by Staphylococcus aureus. Previously reported experiments of PEG equilibrium partitioning into this nanopore show that the charge state of the channel changes the ability of PEG entry in an MW-dependent manner. We explain such an effect by parameter-free calculations of the PEG self-energy from the channel 3D atomic structure that include repulsive dielectrophoretic and hydrostatic forces on the polymer. We found that the pH-induced shift in the measured free energy of partitioning ΔΔGexp from single-channel conductance measurements agrees with calculated energy changes ΔΔEcalc. Our results show that the PEG-sizing technique may need corrections in the case of charged biological pores

A three-dimensional model to describe complete human corneal oxygenation during contact lens wear

We perform a novel 3D study to quantify the corneal oxygen consumption and diffusion in each part of the cornea with different contact lens materials. The oxygen profile is calculated as a function of oxygen tension at the cornea-tear interface and the oxygen transmissibility of the lens, with values used in previous studies. We aim to determine the influence of a detailed geometry of the cornea in their modeling compared to previous low dimensional models used in the literature. To this end, a 3-D study based on an axisymmetric volume element analysis model was applied to different contact lenses currently on the market. We have obtained that the model provides a valuable tool for understanding the flux and cornea oxygen profiles through the epithelium, stroma, and endothelium. The most important results are related to the dependence of the oxygen flux through the cornea-lens system on the contact lens thickness and geometry. Both parameters play an important role in the corneal flux and oxygen tension distribution. The decline in oxygen consumption experienced by the cornea takes place just inside the epithelium, where the oxygen tension falls to between 95 and 16 mmHg under open eye conditions, and 30 to 0.3 mmHg under closed eye conditions, depending on the contact lens worn. This helps to understand the physiological response of the corneal tissue under conditions of daily and overnight contact lens wear, and the importance of detailed geometry of the cornea in the modeling of diffusion for oxygen and other species

Ion transport through biological channels

The transport of ions across single-molecule protein nanochannels is important both in the biological context and in proposed nanotechnological applications. Here we discuss these systems from the perspective of non-equilibrium physics, and in particular, whether the concepts underlying the physics of diffusive and electrokinetic transport can be employed to predict and understand these systems.This work was supported by the Spanish Government (grant FIS2011-1305 1-E) and of University Jaume I grant P1·1B2012-16

Dielectric saturation of water in a membrane protein channel

Water molecules in confined geometries like nanopores and biological ion channels exhibit structural and dynamical properties very different from those found in free solution. Protein channels that open aqueous pores through biological membranes provide a complex spatial and electrostatic environment that decreases the translational and rotational mobility of water molecules, thus altering the effective dielectric constant of the pore water. By using the Booth equation, we study the effect of the large electric field created by ionizable residues of an hour-glass shaped channel, the bacterial porin OmpF, on the pore water dielectric constant, ew. We find a space-dependent significant reduction (down to 20) of ew that may explain some ad hoc assumptions about the dielectric constant of the protein and the water pore made to reconcile model calculations with measurements of permeation properties and pKa’s of protein residues. The electric potential calculations based on the OmpF protein atomic structure and the Booth field-dependent dielectric constant show that protein dielectric constants ca. 10 yield good agreement with molecular dynamics simulations as well as permeation experiment

A three-dimensional model to describe complete human corneal oxygenation during contact lens wear

[EN] We perform a novel 3D study to quantify the corneal oxygen consumption and diffusion in each part of the cornea with different contact lens materials. The oxygen profile is calculated as a function of oxygen tension at the cornea-tear interface and the oxygen transmissibility of the lens, with values used in previous studies. We aim to determine the influence of a detailed geometry of the cornea in their modeling compared to previous low dimensional models used in the literature. To this end, a 3-D study based on an axisymmetric volume element analysis model was applied to different contact lenses currently on the market. We have obtained that the model provides a valuable tool for understanding the flux and cornea oxygen profiles through the epithelium, stroma, and endothelium. The most important results are related to the dependence of the oxygen flux through the cornea-lens system on the contact lens thickness and geometry. Both parameters play an important role in the corneal flux and oxygen tension distribution. The decline in oxygen consumption experienced by the cornea takes place just inside the epithelium, where the oxygen tension falls to between 95 and 16 mmHg under open eye conditions, and 30 to 0.3 mmHg under closed eye conditions, depending on the contact lens worn. This helps to understand the physiological response of the corneal tissue under conditions of daily and overnight contact lens wear, and the importance of detailed geometry of the cornea in the modeling of diffusion for oxygen and other species.This research was funded by the Universitat Jaume I (UJI) under the project UJI-B2018-53. We thanks to Robert Jones for the English language revision.Aguilella-Arzo, M.; Compañ Moreno, V. (2023). A three-dimensional model to describe complete human corneal oxygenation during contact lens wear. Journal of Biomedical Materials Research Part B Applied Biomaterials. 111(3):610-621. https://doi.org/10.1002/jbm.b.35180610621111

Molecular Dynamics simulations of concentrated aqueous electrolyte solutions

Transport properties of concentrated electrolytes have been analyzed using classical molecular dynamics simulations with the algorithms and parameters typical of simulations describing complex electrokinetic phenomena. The electrical conductivity and transport numbers of electrolytes containing monovalent (KCl), divalent (MgCl$_2$), a mixture of both (KCl + MgCl$_2$), and trivalent (LaCl$_3$) cations have been obtained from simulations of the electrolytes in electric fields of different magnitude. The results obtained for different simulation parameters have been discussed and compared with experimental measurements of our own and from the literature. The electroosmotic flow of water molecules induced by the ionic current in the different cases has been calculated and interpreted with the help of the hydration properties extracted from the simulations

Corneal Equilibrium Flux as a Function of Corneal Surface Oxygen Tension

[EN] Purpose Oxygen is essential for aerobic mammalian cell physiology. Oxygen tension (PO2) should reach a minimum at some position within the corneal stroma, and oxygen flux should be zero, by definition, at this point as well. We found the locations and magnitudes of this ¿corneal equilibrium flux¿ (xmin) and explored its physiological implications. Methods We used an application of the Monod kinetic model to calculate xmin for normal human cornea as anterior surface PO2 changes from 155 to 20 mmHg. Results We find that xmin deepens, broadens, and advances from 1.25 ¿m above the endothelial¿aqueous humor surface toward the epithelium (reaching a position 320 ¿m above the endothelial¿aqueous humor surface) as anterior corneal surface PO2 decreases from 155 to 20 mmHg. Conclusions Our model supports an anterior corneal oxygen flux of 9 ¿L O2 · cm¿2 · h¿1 and an epithelial oxygen consumption of approximately 4 ¿L O2 · cm¿2 · h¿1. Only at the highest anterior corneal PO2 does our model predict that oxygen diffuses all the way through the cornea to perhaps reach the anterior chamber. Of most interest, corneal oxygen consumption should be supported down to a corneal surface PO2 of 60 to 80 mmHg but declines below this range. We conclude that the critical oxygen tension for hypoxia induced corneal swelling is more likely this range rather than a fixed value.Compañ Moreno, V.; Aguilella-Arzo, M.; Weissman, BA. (2017). Corneal Equilibrium Flux as a Function of Corneal Surface Oxygen Tension. Optometry and Vision Science. 94(6):672-679. doi:10.1097/OPX.0000000000001083S67267994

Mecànica de fluids i termodinàmica

Enginyeria Tècnica en Disseny Industrial. 502: Físic