Sodium Ion Binding Sites and Hydration in the Lumen of a Bacterial Ion Channel from Molecular Dynamics Simulations

Molecular dynamics (MD) calculations have been used to identify Na⁺ binding sites in the lumen of a bacterial voltage-gated ion channel. MD trajectories have been carried out starting from the recently reported X-ray crystal structure of NavAb in a closed or inactivated conformation. The X-ray structure is stable on the time scale of the MD simulations when equilibrated in a fully hydrated lipid bilayer. Exposure to a 70 mM NaCl solution and a trajectory spanning ∼0.15 μs reveals two locations in the selectivity filter (SF) of the channel, with Na⁺ coordinated to both water molecules and negatively charged protein residues. The nature of the Na⁺ dynamic hydration environment has been explored, and surprisingly water seems to be able to permeate from bulk, via the SF, to the central cavity, whereas Na⁺ ions remain near their primary SF locations, a finding that contrasts with the situation that obtains for potassium channels

Structure, Dynamics, and Spectral Diffusion of Water from First-Principles Molecular Dynamics

We have carried out first-principles Born–Oppenheimer molecular dynamics (BOMD) simulations of heavy water using density functional theory in conjunction with either empirical van der Waals (vdW) corrections or semilocal (van der Waals) exchange and correlation functionals. Specifically, gradient-corrected density functionals (BLYP), semiempirical vdW methods (BLYP-D2, BLYP-D3, PBE-D3, revPBE-D3), and vdW density functionals (DRSLL-PBE, DRSLL-optB88) are applied to evaluate their accuracy in describing the hydrogen-bonded network of heavy water. Ab initio trajectories are used to calculate structural and dynamical properties, with special emphasis on vibrational spectral diffusion and hydrogen bond dynamics. Our results show that inclusion of vdW interactions in DFT-GGA significantly affects the structure of liquid water and results in a faster diffusion. The combination of BLYP and revPBE functionals with the semiempirical vdW method of Grimme et al. [<i>J. Chem. Phys.</i> <b>2010</b>, <i>132</i>, 154104] and modified B88 functionals with the semilocal correlation functional according to M. Dion et al. [<i>Phys. Rev. Lett.</i> <b>2004</b>, <i>92</i>, 246401] provide the best agreement with experiments

Understanding the Boron–Nitrogen Interaction and Its Possible Implications in Drug Design

2-Aminoethoxydiphenylborate (2-APB) is a broad-spectrum modulator of various membrane proteins. Specifically, it exhibits concentration dependent modulation of calcium signaling through store-operated calcium (SOC) channels: low micromolar concentration of 2-APB stimulates SOC entry while a higher concentration induces complete inhibition. Ab initio quantum chemical calculations show that the relative stability of the two major isomers of 2-APB (cyclic and extended) is about 8 kcal/mol. The dual functionality of 2-APB for SOC channels is thus likely associated with its ability to switch among isomeric forms, suited to different binding sites in the SOC channels with distinct binding affinities. Importantly, the moderate relative stability of different isomers results from a delicate balance between the intramolecular boron–nitrogen coordinate bond with strength about −45 kcal/mol and ring strain engendered by cyclic oligomerization. The synergistic effect of these two factors likely makes 2-APB an ideal dual effect drug

X-ray Absorption Spectral Signature of Quantum Nuclei in Liquid Water

<div> <div> <div> <p>Based on electron-hole excitation theory, we investigate the X-ray absorption spectral signature of nuclear quantum effect in liquid water, whose molecular structure is simulated by path-integral molecular dynamics using the MB-pol model. Compared to spectra generated from classically modeled water structure, quantum nuclei has important effect on spectra in terms of both the spectral energies and their line shapes. At the short-range ordering of H-bond network, the delocalized protons increase the fluctuations on the intramolecular covalency and broaden the pre-edge of the spectra. For intermediate-range and long-range orderings, the observed red and blue shifts of the main-edge and post-edge are attributed to the so-called competing quantum effects, under which both the weak and well-formed H-bonds are promoted. The theoretical spectra are in nearly quantitative agreement with the available experimental data. </p> </div> </div> </div

First-Principles Study of Aqueous Hydroxide Solutions

Green open access version of the paper:<div><i>First-Principles Study of Aqueous Hydroxide Solutions</i></div><div>To be cited as:</div><div><i>J. Am. Chem. Soc</i>. <b>2002</b>, <i>124</i>, 8534–8535</div><div>DOI: 10.1021/ja020350g</div><div>Link to the VoR: http://pubs.acs.org/doi/full/10.1021/ja020350g</div><div><br></div><div>Popular summary at: https://goo.gl/6mMWuP</div><div><br><div>This contribution was uploaded during the Open Access Week 2016 and is meant to be a little concrete step to put "Open in Action".</div></div

Micellization Studied by GPU-Accelerated Coarse-Grained Molecular Dynamics

The computational design of advanced materials based on surfactant self-assembly without ever stepping foot in the laboratory is an important goal, but there are significant barriers to this approach, because of the limited spatial and temporal scales accessible by computer simulations. In this paper, we report our work to bridge the gap between laboratory and computational time scales by implementing the coarse-grained (CG) force field previously reported by Shinoda et al. [Shinoda, W.; DeVane, R.; Klein, M. L. <i>Mol. Simul</i>. <b>2007</b>, <i>33</i>, 27–36] into the HOOMD-Blue graphical processing unit (GPU)-accelerated molecular dynamics (MD) software package previously reported by Anderson et al. [Anderson, J. A.; Lorenz, C. D.; Travesset, A. <i>J. Comput. Phys</i>. <b>2008</b>, <i>227</i>, 5342–5359]. For a system of 25 750 particles, this implementation provides performance on a single GPU, which is superior to that of a widely used parallel MD simulation code running on an optimally sized CPU-based cluster. Using our GPU setup, we have collected 0.6 ms of MD trajectory data for aqueous solutions of 7 different nonionic polyethylene glycol (PEG) surfactants, with most of the systems studied representing ∼1 000 000 atoms. From this data, we calculated various properties as a function of the length of the hydrophobic tails and PEG head groups. Specifically, we determined critical micelle concentrations (CMCs), which are in good agreement with experimental data, and characterized the size and shape of micelles. However, even with the microsecond trajectories employed in this study, we observed that the micelles composed of relatively hydrophobic surfactants are continuing to grow at the end of our simulations. This suggests that the final micelle size distributions of these systems are strongly dependent on initial conditions and that either longer simulations or advanced sampling techniques are needed to properly sample their equilibrium distributions. Nonetheless, the combination of coarse-grained modeling and GPU acceleration marks a significant step toward the computational prediction of the thermodynamic properties of slowly evolving surfactant systems

Ion Channel Sensing: Are Fluctuations the Crux of the Matter?

The nonselective cation channel TRPV1 is responsible for transducing noxious stimuli into action potentials propagating through peripheral nerves. It is activated by temperatures greater than 43 °C, while remaining completely nonconductive at temperatures lower than this threshold. The origin of this sharp response, which makes TRPV1 a biological temperature sensor, is not understood. Here we used molecular dynamics simulations and free energy calculations to characterize the molecular determinants of the transition between nonconductive and conductive states. We found that hydration of the pore and thus ion permeation depends critically on the polar character of its molecular surface: in this narrow hydrophobic enclosure, the motion of a polar side-chain is sufficient to stabilize either the dry or wet state. The conformation of this side-chain is in turn coupled to the hydration state of four peripheral cavities, which undergo a dewetting transition at the activation temperature

Flavonoids from <i>Perovskia atriplicifolia</i> and Their in Vitro Displacement of the Respective Radioligands for Human Opioid and Cannabinoid Receptors

Bioassay-guided fractionation of the leaves of <i>Perovskia atriplicifolia</i> (Russian sage) resulted in the isolation of four previously known flavonoid derivatives, 5-hydroxy-6,7,3′,4′-tetramethoxyflavone (<b>1</b>), 5,7-dihydroxy-6,3′,4′-trimethoxyflavone (<b>2</b>), 5-hydroxy-6,7,4′-trimethoxyflavone (<b>3</b>), and 5,7-dihydroxy-6,4′-dimethoxyflavone (<b>4</b>). Compounds <b>1</b>,<b> 3</b>, and <b>4</b> showed displacement of the radioligand for the cloned human δ opioid receptor with <i>K</i>_i values ranging from 3.1 to 26.0 μM. In addition, the binding mode of the compounds in the active site of the δ opioid receptor was investigated through molecular modeling algorithms. This study may have implications in better understanding non-nitrogenous δ opioid receptor ligands

Effect of Interlayer Spacing on the Activity of Layered Manganese Oxide Bilayer Catalysts for the Oxygen Evolution Reaction

We investigated the dependence of the electrocatalytic activity for the oxygen evolution reaction (OER) on the interlayer distance of five compositionally distinct layered manganese oxide nanostructures. Each individual electrocatalyst was assembled with a different alkali metal intercalated between two nanosheets (NS) of manganese oxide to form a bilayer structure. Manganese oxide NS were synthesized via the exfoliation of a layered material, birnessite. Atomic force microscopy was used to determine the heights of the bilayer catalysts. The interlayer spacing of the supported bilayers positively correlates with the size of the alkali cation: NS/Cs⁺/NS > NS/Rb⁺/NS > NS/K⁺/NS > NS/Na⁺/NS > NS/Li⁺/NS. The thermodynamic origins of these bilayer heights were investigated using molecular dynamics simulations. The overpotential (η) for the OER correlates with the interlayer spacing; NS/Cs⁺/NS has the lowest η (0.45 V), while NS/Li⁺/NS exhibits the highest η (0.68 V) for OER at a current density of 1 mA/cm². Kinetic parameters (η and Tafel slope) associated with NS/Cs⁺/NS for the OER were superior to that of the bulk birnessite phase, highlighting the structural uniqueness of these nanoscale assemblies

Complex Arrangement of Orthogonal Nanoscale Columns <i>via</i> a Supramolecular Orientational Memory Effect

Memory effects, including shape, chirality, and liquid-crystallinity, have enabled macroscopic materials with novel functions. However, the generation of complex supramolecular nanosystems <i>via</i> memory effects has not yet been investigated. Here, we report a cyclotriveratrylene-crown (CTV) compound that self-assembles into supramolecular columns and spheres forming, respectively, hexagonal and cubic mesophases. Upon transition from one phase to the other, an epitaxial relationship holds, <i>via</i> an unprecedented supramolecular orientational memory effect. Specifically, the molecular orientation and columnar character of supramolecular packing is preserved in the cubic phase, providing an otherwise inaccessible structure comprising orthogonally oriented domains of supramolecular columns. The continuous columnar character of tetrahedrally distorted supramolecular spheres self-organized from the CTV derivative in the faces of the <i>Pm</i>3̅<i>n</i> lattice is the basis of this supramolecular orientational memory, which holds throughout cycling in temperature between the two phases. This concept is expected to be general for other combinations of periodic and quasiperiodic arrays generated from supramolecular spheres upon transition to supramolecular columns