Permeability of a Fluid Lipid Bilayer to Short-Chain Alcohols from First Principles

Computational prediction of membrane permeability to small molecules requires accurate description of both the thermodynamics and kinetics underlying translocation across the lipid bilayer. In this contribution, well-converged, microsecond-long free-energy calculations are combined with a recently developed subdiffusive kinetics framework to describe the membrane permeation of a homologous series of short-tail alcohols, from methanol to 1-butanol, with unprecedented fidelity to the underlying molecular models. While the free-energy profiles exhibit barriers for passage through the center of the bilayer in all cases, the height of these barriers decreases with the length of the aliphatic chain of the alcohol, in quantitative agreement with experimentally determined differential solvation free energies in water and oil. A unique aspect of the subdiffusive model employed herein, which was developed in a previous article, is the determination of a position-dependent fractional order which quantifies the degree to which the motion of the alcohol deviates from classical diffusion along the thickness of the membrane. In the aqueous medium far from the bilayer, this quantity approaches 1.0, the asymptotic limit for purely classical diffusion, whereas it dips below 0.75 near the center of the membrane irrespective of the permeant. Remarkably, the fractional diffusivity near the center of membrane, where its influence on the permeability is the greatest, is similar among the four permeants despite the large difference in molecular weight and lipophilicity between methanol and 1-butanol. The relative permeabilities, which are estimated from the free-energy and fractional diffusivity profiles, are therefore determined predominantly by differences in the former rather than the latter. The predicted relative permeabilities are highly correlated with existing experimental results, albeit they do not agree quantitatively with them. On the other hand, quite unexpectedly, the reported experimental values for the short-tail alcohols are nearly three orders of magnitude lower than the available experimental measurement for water. Plausible explanations for this apparent disagreement between theory and experiment are considered in detail

A high-dimensional neural network potential for molecular dynamics simulations of condensed phase nickel and phase transitions

A high-dimensional neural network interatomic potential was developed and used in molecular dynamics simulations of condensed phase Ni and Ni systems with liquid–solid phase coexistence. The reference data set was generated by sampling the potential energy surface over a broad temperature-pressure domain using ab initio MD simulations to train a unified potential. Excellent agreement was achieved between bulk face-centred cubic nickel thermal expansion simulations and relevant experimental data. The same potential also yields accurate structures and diffusivities in the liquid state. The phase transition between liquid and solid phases was simulated using the two-phase interface method. The predicted melting point temperature is within a few kelvins of the literature value. The general methodology could be applied to describe crystals with much more complex phase behaviours.</p

Iodide Binding in Sodium-Coupled Cotransporters

Several apical iodide translocation pathways have been proposed for iodide efflux out of thyroid follicular cells, including a pathway mediated by the sodium-coupled monocarboxylate transporter 1 (SMCT1), which remains controversial. Herein, we evaluate structural and functional similarities between SMCT1 and the well-studied sodium-iodide symporter (NIS) that mediates the first step of iodide entry into the thyroid. Free-energy calculations using a force field with electronic polarizability verify the presence of a conserved iodide-binding pocket between the TM2, TM3, and TM7 segments in hNIS, where iodide is coordinated by Phe67, Gln72, Cys91, and Gln94. We demonstrate the mutation of residue Gly93 of hNIS to a larger amino acid expels the side chain of a critical tryptophan residue (Trp255) into the interior of the binding pocket, partially occluding the iodide binding site and reducing iodide affinity, which is consistent with previous reports associating mutation of this residue with iodide uptake deficiency and hypothyroidism. Furthermore, we find that the position of Trp255 in this hNIS mutant mirrors that of Trp253 in wild-type hSMCT1, where a threonine (Thr91) occupies the position homologous to that occupied by glycine in wild-type hNIS (Gly93). Correspondingly, mutation of Thr91 to glycine in hSMCT1 makes the pocket structure more like that of wild-type hNIS, increasing its iodide affinity. These results suggest that wild-type hSMCT1 in the inward-facing conformation may bind iodide only very weakly, which may have implications for its ability to transport iodide

Diffusive Models of Membrane Permeation with Explicit Orientational Freedom

Accurate calculation of permeabilities from first-principles has been a long-standing challenge for computer simulations, notably in the context of drug discovery, as a route to predict the propensity of small, organic molecules to spontaneously translocate biological membranes. Of equal importance is the understanding of the permeation process and the pathway followed by the permeant from the aqueous medium to the interior of the lipid bilayer, and back out again. A convenient framework for the computation of permeabilities is provided by the solubility–diffusion model, which requires knowledge of the underlying free-energy and diffusivity landscapes. Here, we develop a formalism that includes an explicit description of the orientational motion of the solute as it diffuses across the membrane. Toward this end, we have generalized a recently proposed method that reconciles thermodynamics and kinetics in importance-sampling simulations by means of a Bayesian-inference scheme to reverse-solve the underlying Smoluchowski equation. Performance of the proposed formalism is examined in the model cases of a water and an ethanol molecule crossing a fully hydrated lipid bilayer. Our analysis reveals a conspicuous dependence of the free-energy and rotational diffusivity on the orientation of ethanol when it lies within the headgroup region of the bilayer. Specifically, orientations for which the hydroxyl group lies among the polar lipid head groups, while the ethyl group recedes toward the hydrophobic interior are associated with free-energy minima ∼2<i>k</i>_B<i>T</i> deep, as well as significantly slower orientational kinetics compared to the bulk solution or the core of the bilayer. The conspicuous orientational anisotropy of ethanol at the aqueous interface is suggestive of a complete rotation of the permeant as it crosses the hydrophobic interior of the membrane

Calculating Position-Dependent Diffusivity in Biased Molecular Dynamics Simulations

Calculating transition rates and other kinetic quantities from molecular simulations requires knowledge not only of the free energy along the relevant coordinate but also the diffusivity as a function of that coordinate. A variety of methods are currently used to map the free-energy landscape in molecular simulations; however, simultaneous calculation of position-dependent diffusivity is complicated by biasing forces applied with many of these methods. Here, we describe a method to calculate position-dependent diffusivities in simulations including known time-dependent biasing forces, which relies on a previously proposed Bayesian inference scheme. We first apply the method to an explicitly diffusive model, and then to an equilibrium molecular dynamics simulation of liquid water including a position-dependent thermostat, comparing the results to those of an established method. Finally, we test the method on a system of liquid water, where oscillations of the free energy along the coordinate of interest preclude sufficient sampling in an equilibrium simulation. The adaptive biasing force method permits roughly uniform sampling along this coordinate, while the method presented here gives a consistent result for the position-dependent diffusivity, even in a short simulation where the adaptive biasing force is only partially converged

Sonoporation at Small and Large Length Scales: Effect of Cavitation Bubble Collapse on Membranes

Ultrasound has emerged as a promising means to effect controlled delivery of therapeutic agents through cell membranes. One possible mechanism that explains the enhanced permeability of lipid bilayers is the fast contraction of cavitation bubbles produced on the membrane surface, thereby generating large impulses, which, in turn, enhance the permeability of the bilayer to small molecules. In the present contribution, we investigate the collapse of bubbles of different diameters, using atomistic and coarse-grained molecular dynamics simulations to calculate the force exerted on the membrane. The total impulse can be computed rigorously in numerical simulations, revealing a superlinear dependence of the impulse on the radius of the bubble. The collapse affects the structure of a nearby immobilized membrane, and leads to partial membrane invagination and increased water permeation. The results of the present study are envisioned to help optimize the use of ultrasound, notably for the delivery of drugs

Water Conduction through a Peptide Nanotube

When inserted into lipid bilayers, synthetic channels formed by cyclic peptides of alternated d- and l-α-amino acids have been shown to modulate the permeability of the cell wall, thereby endowing them with potential bactericidal capability. Details of the underlying energetics of the permeation events remain, however, only fragmentary. Water conduction in a peptide nanotube formed by eight <i>cyclo</i>-(<u>L</u>W)₄ subunits embedded in a fully hydrated palmitoyloleylphosphatidylcholine bilayer has been investigated using molecular-dynamics simulations with a time-dependent bias. The topology of the reconstructed free-energy landscape delineating the transport of water mirrors the arrangement of the cyclic peptides in the open-ended tubular structure. Within the nanotube, the small, periodic free-energy barriers, on the order of <i>k</i>_B<i>T</i>, arising between adjacent peptide subunits, are suggestive of unhampered translocation. It still remains that translational diffusion of water in the hollow cylindrical cavity is necessarily affected by its interaction with the accessible polar moieties of the constituent d- and l-α-amino acids. By combining diffusivity measurements with the free-energy landscape, we put forth a reaction-rate theory to describe the conduction kinetics of water inside the peptide nanotube

Assessing Graphene Nanopores for Sequencing DNA

Using all-atom molecular dynamics and atomic-resolution Brownian dynamics, we simulate the translocation of single-stranded DNA through graphene nanopores and characterize the ionic current blockades produced by DNA nucleotides. We find that transport of single DNA strands through graphene nanopores may occur in single nucleotide steps. For certain pore geometries, hydrophobic interactions with the graphene membrane lead to a dramatic reduction in the conformational fluctuations of the nucleotides in the nanopores. Furthermore, we show that ionic current blockades produced by different DNA nucleotides are, in general, indicative of the nucleotide type, but very sensitive to the orientation of the nucleotides in the nanopore. Taken together, our simulations suggest that strand sequencing of DNA by measuring the ionic current blockades in graphene nanopores may be possible, given that the conformation of DNA nucleotides in the nanopore can be controlled through precise engineering of the nanopore surface

Microscopic Perspective on the Adsorption Isotherm of a Heterogeneous Surface

Adsorption of dissolved molecules onto solid surfaces can be extremely sensitive to the atomic-scale properties of the solute and surface, causing difficulties for the design of fluidic systems in industrial, medical, and technological applications. In this communication, we show that the Langmuir isotherm for adsorption of a small molecule to a realistic, heterogeneous surface can be predicted from atomic structures of the molecule and surface through molecular dynamics (MD) simulations. We highlight the method by studying the adsorption of dimethyl methylphosphonate (DMMP) to amorphous silica substrates and show that subtle differences in the atomic-scale surface properties can have drastic effects on the Langmuir isotherm. The sensitivity of the method presented is sufficient to permit the optimization of fluidic devices and to determine fundamental design rules for controlling adsorption at the nanoscale

Assessing Graphene Nanopores for Sequencing DNA

Using all-atom molecular dynamics and atomic-resolution Brownian dynamics, we simulate the translocation of single-stranded DNA through graphene nanopores and characterize the ionic current blockades produced by DNA nucleotides. We find that transport of single DNA strands through graphene nanopores may occur in single nucleotide steps. For certain pore geometries, hydrophobic interactions with the graphene membrane lead to a dramatic reduction in the conformational fluctuations of the nucleotides in the nanopores. Furthermore, we show that ionic current blockades produced by different DNA nucleotides are, in general, indicative of the nucleotide type, but very sensitive to the orientation of the nucleotides in the nanopore. Taken together, our simulations suggest that strand sequencing of DNA by measuring the ionic current blockades in graphene nanopores may be possible, given that the conformation of DNA nucleotides in the nanopore can be controlled through precise engineering of the nanopore surface