213 research outputs found
Liquid-vapor oscillations of water in hydrophobic nanopores
Water plays a key role in biological membrane transport. In ion channels and
water-conducting pores (aquaporins), one dimensional confinement in conjunction
with strong surface effects changes the physical behavior of water. In
molecular dynamics simulations of water in short (0.8 nm) hydrophobic pores the
water density in the pore fluctuates on a nanosecond time scale. In long
simulations (460 ns in total) at pore radii ranging from 0.35 nm to 1.0 nm we
quantify the kinetics of oscillations between a liquid-filled and a
vapor-filled pore. This behavior can be explained as capillary evaporation
alternating with capillary condensation, driven by pressure fluctuations in the
water outside the pore. The free energy difference between the two states
depends linearly on the radius. The free energy landscape shows how a
metastable liquid state gradually develops with increasing radius. For radii
larger than ca. 0.55 nm it becomes the globally stable state and the vapor
state vanishes. One dimensional confinement affects the dynamic behavior of the
water molecules and increases the self diffusion by a factor of two to three
compared to bulk water. Permeabilities for the narrow pores are of the same
order of magnitude as for biological water pores. Water flow is not continuous
but occurs in bursts. Our results suggest that simulations aimed at collective
phenomena such as hydrophobic effects may require simulation times longer than
50 ns. For water in confined geometries, it is not possible to extrapolate from
bulk or short time behavior to longer time scales.Comment: 20 pages, 4 figures, 3 tables; to be published in Proc. Natl. Acad.
Sci. US
Intermittent permeation of cylindrical nanopores by water
Molecular Dynamics simulations of water molecules in nanometre sized
cylindrical channels connecting two reservoirs show that the permeation of
water is very sensitive to the channel radius and to electric polarization of
the embedding material. At threshold, the permeation is {\emph{intermittent}}
on a nanosecond timescale, and strongly enhanced by the presence of an ion
inside the channel, providing a possible mechanism for gating. Confined water
remains surprisingly fluid and bulk-like. Its behaviour differs strikingly from
that of a reference Lennard-Jones fluid, which tends to contract into a highly
layered structure inside the channel.Comment: 4 pages, 4 figure
A Hydrophobic Gate in an Ion Channel: The Closed State of the Nicotinic Acetylcholine Receptor
The nicotinic acetylcholine receptor (nAChR) is the prototypic member of the
`Cys-loop' superfamily of ligand-gated ion channels which mediate synaptic
neurotransmission, and whose other members include receptors for glycine,
gamma-aminobutyric acid, and serotonin. Cryo-electron microscopy has yielded a
three dimensional structure of the nAChR in its closed state. However, the
exact nature and location of the channel gate remains uncertain. Although the
transmembrane pore is constricted close to its center, it is not completely
occluded. Rather, the pore has a central hydrophobic zone of radius about 3 A.
Model calculations suggest that such a constriction may form a hydrophobic
gate, preventing movement of ions through a channel. We present a detailed and
quantitative simulation study of the hydrophobic gating model of the nicotinic
receptor, in order to fully evaluate this hypothesis. We demonstrate that the
hydrophobic constriction of the nAChR pore indeed forms a closed gate.
Potential of mean force (PMF) calculations reveal that the constriction
presents a barrier of height ca. 10 kT to the permeation of sodium ions,
placing an upper bound on the closed channel conductance of 0.3 pS. Thus, a 3 A
radius hydrophobic pore can form a functional barrier to the permeation of a 1
A radius Na+ ion. Using a united atom force field for the protein instead of an
all atom one retains the qualitative features but results in differing
conductances, showing that the PMF is sensitive to the detailed molecular
interactions.Comment: Accepted by Physical Biology; includes a supplement and a
supplementary mpeg movie can be found at
http://sbcb.bioch.ox.ac.uk/oliver/download/Movies/watergate.mp
Topological dissection of the membrane transport protein Mhp1 derived from cysteine accessibility and mass spectrometry
Cys accessibility and quantitative intact mass spectrometry (MS) analyses have been devised to study the topological transitions of Mhp1, the membrane protein for sodium-linked transport of hydantoins from Microbacterium liquefaciens. Mhp1 has been crystallised in three forms (outward-facing open, outward-facing occluded with substrate bound, and inward-facing open). We show that one natural cysteine residue, Cys327, out of three, has an enhanced solvent accessibility in the inward-facing (relative to the outward-facing) form. Reaction of the purified protein, in detergent, with the thiol-reactive N-ethylmalemide (NEM), results in modification of Cys327, suggesting that Mhp1 adopts predominantly inward-facing conformations. Addition of either sodium ions or the substrate 5-benzyl-L-hydantoin (L-BH) does not shift this conformational equilibrium, but, systematic co-addition of the two results in an attenuation of labelling, indicating a shift toward outward-facing conformations that can be interpreted using conventional enzyme kinetic analyses. Such measurements can afford the Km for each ligand as well as the stoichiometry of ion-substrate coupled conformational changes. Mutations that perturb the substrate binding site either result in the protein being unable to adopt outward-facing conformations or in a global destabilisation of structure. The methodology combines covalent labeling, mass spectrometry and kinetic analyses in a straightforward workflow applicable to a range of systems, enabling the interrogation of changes in a protein’s conformation required for function at varied concentrations of substrates, and the consequences of mutations on these conformational transitions
Preferential Solvation within Hydrophilic Nanocavities and Its Effect on the Folding of Cholate Foldamers
First principles elastic constants and electronic structure of alpha-Pt_2Si and PtSi
We have carried out a first principles study of the elastic properties and
electronic structure for two room-temperature stable Pt silicide phases,
tetragonal alpha-Pt_2Si and orthorhombic PtSi. We have calculated all of the
equilibrium structural parameters for both phases: the a and c lattice
constants for alpha-Pt_2Si and the a, b, and c lattice constants and four
internal structural parameters for PtSi. These results agree closely with
experimental data. We have also calculated the zero-pressure elastic constants,
confirming prior results for pure Pt and Si and predicting values for the six
(nine) independent, non-zero elastic constants of alpha-Pt_2Si (PtSi). These
calculations include a full treatment of all relevant internal displacements
induced by the elastic strains, including an explicit determination of the
dimensionless internal displacement parameters for the three strains in
alpha-Pt_2Si for which they are non-zero. We have analyzed the trends in the
calculated elastic constants, both within a given material as well as between
the two silicides and the pure Pt and Si phases. The calculated electronic
structure confirms that the two silicides are poor metals with a low density of
states at the Fermi level, and consequently we expect that the Drude component
of the optical absorption will be much smaller than in good metals such as pure
Pt. This observation, combined with the topology found in the first principles
spin-orbit split band structure, suggests that it may be important to include
the interband contribution to the optical absorption, even in the infrared
region.Comment: v1: 27 pages, 7 figures, 13 tables submitted to Phys. Rev. B v2: 10
pages, 4 figures, 12 tables (published in Phys. Rev B) contains only
ab-initio calculations; valence force field models are now in a separate
paper: cond-mat/010618
Inherent Dynamics of the Acid-Sensing Ion Channel 1 Correlates with the Gating Mechanism
A combination of computational and experimental approaches reveals the dynamics of ASIC1 gating, involving a deformation of the channel that triggers “twist-to-open” motions of the channel pore
Elastic and thermodynamic properties of alpha-Bi2O3 at high pressures: Study of mechanical and dynamical stability
[EN] The elastic and thermodynamic properties of the monoclinic polymorph of bismuth oxide (alpha-Bi2O3); aka mineral bismite, have been theoretically investigated both at room pressure and under hydrostatic compression by means of first principles calculations based on density functional theory. In this work, the elastic stiffness coefficients, elastic moduli, Poisson's ratio, B/G ratio, elastic anisotropy indexes (A(B), A(G), A(1), A(2), A(3), Au) and directional dependence of Young modulus and linear compressibility have been obtained. Vickers hardness, and sound wave velocities have been calculated. Our simulations show that bismite has a high elastic anisotropy. alpha-Bi2O3 is a ductile material whose elastic anisotropy increases under compression and presents a stronger ability to resist volume compression than shear deformation at all pressures. Besides, it has a very small minimum thermal conductivity, which is well suited for thermoelectric applications. Finally, the mechanical and dynamical stability of bismite at high pressure has been studied and it has been found that alpha-Bi2O3 becomes mechanically unstable at pressures beyond 19.3 GPa and dynamically unstable above 11.5 GPa. These instabilities could be responsible for the amorphization of bismite observed experimentally between 15 and 20 GPa.This research was supported by the Spanish Ministerio de Economia y Competitividad under Projects MAT2016-75586-C4-2-P/3-P and MAT2015-71070-REDC. P.R.-H. and A.M. acknowledge Red Espanola de SupercomputaciOn (RES) and MALTA-Cluster for the computing time.Gomis, O.; Manjón, F.; Rodríguez-Hernández, P.; Muñoz, A. (2019). Elastic and thermodynamic properties of alpha-Bi2O3 at high pressures: Study of mechanical and dynamical stability. Journal of Physics and Chemistry of Solids. 124:111-120. https://doi.org/10.1016/j.jpcs.2018.09.002S11112012
InBO3 and ScBO3 at high pressures: an ab initio study of elastic and thermodynamic properties
We have theoretically investigated the elastic properties of calcite-type orthoborates ABO(3) (A= Sc and In) at high pressure by means of ab initio total-energy calculations. From the elastic stiffness coefficients, we have obtained the elastic moduli (B, G and E), Poisson's ratio (nu), B/G ratio, universal elastic anisotropy index (A(U)), Vickers hardness, and sound wave velocities for both orthoborates. Our simulations show that both borates are more resistive to volume compression than to shear deformation (B > G). Both compounds are ductile and become more ductile, with an increasing elastic anisotropy, as pressure increases. We have also calculated some thermodynamic properties, like Debye temperature and minimum thermal conductivity. Finally, we have evaluated the theoretical mechanical stability of both borates at high hydrostatic pressures. It has been found that the calcite-type structure of InBO3 and ScBO3 becomes mechanically unstable at pressures beyond 56.2 and 57.7 GPa, respectively. (C) 2016 Elsevier Ltd. All rights reserved.This study is supported by the Spanish MICINN projects MAT2013-46649-C4-2-P/3-P and MAT2015-71070-REDC. H.M.O., A.M., and P.R-H. acknowledge computing time provided by Red Espanola de Supercomputacion (RES) and MALTA-Cluster. J.A.S. acknowledges Juan de la Cierva fellowship program for financial support.Gomis, O.; Ortiz, HM.; Sans Tresserras, JÁ.; Manjón Herrera, FJ.; Santamaría-Pérez, D.; Rodríguez-Hernández, P.; Muñoz, A. (2016). InBO3 and ScBO3 at high pressures: an ab initio study of elastic and thermodynamic properties. Journal of Physics and Chemistry of Solids. 98:198-208. https://doi.org/10.1016/j.jpcs.2016.07.002S1982089
Modulation of the <i>Neisseria gonorrhoeae </i>drug efflux conduit MtrE
We acknowledge funding through the Wellcome Trust Interdisciplinary Research Funds (grant WT097818MF), the Scottish Universities’ Physics Alliance (SUPA), Tenovus Tayside (grant T16/30) and the Tayside Charitable Trust. O.N.V. has been funded through a BBSRC CASE award (BB/J013072/1).Widespread antibiotic resistance, especially of Gram-negative bacteria, has become a severe concern for human health. Tripartite efflux pumps are one of the major contributors to resistance in Gram-negative pathogens, by efficiently expelling a broad spectrum of antibiotics from the organism. In Neisseria gonorrhoeae, one of the first bacteria for which pan-resistance has been reported, the most expressed efflux complex is MtrCDE. Here we present the electrophysiological characterisation of the outer membrane component MtrE and the membrane fusion protein MtrC, obtained by a combination of planar lipid bilayer recordings and in silico techniques. Our in vitro results show that MtrE can be regulated by periplasmic binding events and that the interaction between MtrE and MtrC is sufficient to stabilize this complex in an open state. In contrast to other efflux conduits, the open complex only displays a slight preference for cations. The maximum conductance we obtain in the in vitro recordings is comparable to that seen in our computational electrophysiology simulations conducted on the MtrE crystal structure, indicating that this state may reflect a physiologically relevant open conformation of MtrE. Our results suggest that the MtrC/E binding interface is an important modulator of MtrE function, which could potentially be targeted by new efflux inhibitors.Publisher PDFPeer reviewe
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