[Show abstract][Hide abstract] ABSTRACT: At present, the three-dimensional structure of the multimeric paracellular claudin pore is unknown. Using extant biophysical data concerning the size of the pore and permeation of water and cations through it, two three-dimensional models of the pore are constructed in silico. Molecular Dynamics (MD) calculations are then performed to compute water and sodium ion permeation fluxes under the influence of applied hydrostatic pressure. Comparison to experiment is made, under the assumption that the hydrostatic pressure applied in the simulations is equivalent to osmotic pressure induced in experimental measurements of water/ion permeability. One model, in which pore-lining charged is distributed evenly over a selectivity filter section 10-16 Å in length, is found to be generally consistent with experimental data concerning the dependence of water and ion permeation on channel pore diameter, pore length and the sign and magnitude of pore lining charge. The molecular coupling mechanism between water and ion flow under conditions where hydrostatic pressure is applied is computationally elucidated. This article is protected by copyright. All rights reserved.
Full-text · Article · Dec 2015 · Proteins Structure Function and Bioinformatics
[Show abstract][Hide abstract] ABSTRACT: Polymer-grafted surfaces and channels are increasingly used for design of responsive materials and sensors due to robust performance and ease of use. Various strategies for control of the nanoscale morphologies of such materials and devices are being tested. Entropic repulsion between the polymer chains in a grafted brush of sufficient density causes the chains to extend in the direction perpendicular to the grafting surface compared to unattached polymers. When nanoparticles having attractive interactions with the polymers are introduced into the solvent, these nanoparticles tend to infiltrate into the brush and reduce its extension. Under certain conditions, sharp reduction in brush height extension can occur over a narrow range of nanoparticle concentration in solution. We describe a way of controlling transport through polymer-functionalized nano-channels with nanoparticle additives, relying on the physics of nanoparticles and polymer brushes under confinement, and we suggest a blueprint for the creation of a tunable nano-valve. The nano-valve is modeled as a cylinder with a polymer brush grafted on its inside surface. Brush properties such as the chain length and the grafting density are chosen so that the brush chains extend into the center of the cylinder in the absence of nanoparticles, occluding the flux of analyte molecules through the pore. When nanoparticles that are attracted to the polymers are introduced into solution, they infiltrate into the brush and partially collapse it against the cylindrical grafting surface, opening up space in the center of the cylinder through which analyte molecules can flow. The operation of such a nano-valve is analyzed via self-consistent field theory calculations in the strong stretching approximation. Self-consistent field analysis is supported by Langevin dynamics simulations of the underlying coarse-grained model of the polymer-nanoparticle system.
Full-text · Article · Jul 2015 · The Journal of Physical Chemistry B
[Show abstract][Hide abstract] ABSTRACT: Influx of ferrous ions from the cytoplasm through 3-fold pores in the shell of ferritin protein is computed using a 3-dimensional Poisson-Nernst-Planck electrodiffusion model, with inputs such as the pore structure and the diffusivity profile of permeant Fe(2+) ions extracted from all-atom Molecular Dynamics (MD) simulations. These calculations successfully reproduce experimental estimates of the transit time of Fe(2+) through the ferritin coat, which is on the millisecond time scale and hence much too long to be directly simulated via all-atom MD. This is also much longer than the typical time scale for ion transit in standard membrane spanning ion channels whose pores bear structural similarity to that of the 3-fold ferritin pore. The slow time scale for Fe(2+) transport through ferritin pores is traced to two features that distinguish the ferritin pore system from standard ion channels, namely i) very low concentration of cytoplasmic Fe(2+) under physiological conditions and ii) very small internal diffusivity coefficients for ions inside the ferritin pore resulting from factors that include the divalent nature of Fe(2+) and two rings of negatively charged amino acids surrounding a narrow geometric obstruction within the ferritin pore interior.
Full-text · Article · Feb 2014 · The Journal of Physical Chemistry A
[Show abstract][Hide abstract] ABSTRACT: Addition of nanoparticles can control the morphologies of grafted polymer layers that are important in a variety of natural and artificial systems. We study the morphologies of grafted polymer layers interacting attractively with nanoparticle inclusions, as a function of particle size and the interaction strength, using self-consistent field theory and Langevin Dynamics simulations. We find that addition of nanoparticles causes distinctive changes in the layer morphology. For sufficiently strong interaction/binding, increasing the concentration of nanoparticles causes a compression of the polymer layer into a compact, low height state, followed by a subsequent rebound and swelling at sufficiently high concentrations. For nanoparticles of small size, the compression of the layer is sharp and occurs over a narrow range of nanoparticle concentrations. The transition region widens as the nanoparticle size increases. The transition is initiated via a dense layer of tightly bound monomers and nanoparticles near the grafting surface, with a low density region above it. For nanoparticles much larger than the characteristic graft spacing in the brush, the behavior is reversed: the nanoparticles penetrate only the dilute region near the top of the polymer layer without causing the layer to collapse.
[Show abstract][Hide abstract] ABSTRACT: A coarse graining method based on the partitioning of atoms into compact flexible clusters is used to formulate the dynamics of the non-equilibrium response of a protein to ligand dissociation. The alpha carbon positions are used as the degrees of freedom. The net stiffness between each pair of neighboring alpha carbons is calculated for the quasi-static, overdamped regime within the harmonic (quadratic potential energy surface) using the equivalent stiffness matrix of the network of atoms occupying the intervening space within the locally interacting region. This localized approach realizes a divide and conquer strategy that results in a substantial reduction in computational complexity while accurately predicting relaxations under general loading conditions. A close correlation between the shapes and timescales of the relaxation curves of the coarse grained and all atom instances of two medium sized proteins, T4 Lysozyme and Ferric Binding Protein (each of which having known apo and holo structures), was observed for the holo to the apo transitions. Furthermore, for both proteins the dominant modes of motion and the decay rates of the temporal relaxation profiles monitoring the separation distance between select amino acid pairs were found to be nearly identical when calculated on the coarse-grained and all-atom scales. Keywords: Langevin, Brownian Mode, Flexible Cluster, Harmonic, Coarse Grain.
No preview · Article · May 2013 · The Journal of Physical Chemistry B
[Show abstract][Hide abstract] ABSTRACT: The effect of optical transmission through an array of vortices in a type-II superconducting film subjected to a strong magnetic field is analyzed. The mechanism responsible for this effect is resonance transmission between two surface plasmon polaritons (SPPs) in the system. The SPP band gap in the system is studied as a function of magnetic field. The transmittance through a system consisting of one vortex embedded in such a film is computed using the finite difference time domain method. The control of transmission by varying magnetic field is analyzed. Applications of the studied phenomena for developing tunable sensors are discussed.
Full-text · Article · Apr 2013 · Journal of the Optical Society of America B
[Show abstract][Hide abstract] ABSTRACT: We study the mechanism of vacancy migration and phase transitions of 3D crystalline colloidal arrays (CCA) using Langevin dynamics simulations. We calculate the self-diffusion coefficient of the colloid particles and the diffusion constant for vacancies as a function of temperature and DLVO potential parameters. We investigate the phase behavior of several systems with different interaction potential parameters using Voronoi analysis. Voronoi polyhedra tessellation, which is a useful method for characterizing the nearest neighbor environment around each atom, provides an efficient and effective way to identify phase transitions as well as geometrical changes in crystals. Using Voronoi analysis, we show that several neighboring particles are involved in the vacancy migration process that causes the vacancy to diffuse.
Full-text · Article · Feb 2013 · The Journal of Physical Chemistry B
[Show abstract][Hide abstract] ABSTRACT: An invertebrate glutamate-gated chloride channel (GluCl) has recently been crystallized in an open-pore state. This channel is homologous to the human Cys-loop receptor family of pentameric ligand-gated ion channels, including anion-selective GlyR and GABAR and cation-selective nAChR and 5HT3. We implemented molecular dynamics (MD) in conjunction with an elastic network model to perturb the x-ray structure of GluCl and investigated the open channel stability and its ion permeation characteristics. Our study suggests that TM2 helical tilting may close GluCl near the hydrophobic constriction L254 (L9'), similar to its cation-selective homologs. Ion permeation characteristics were determined by Brownian dynamics simulations using a hybrid MD/continuum electrostatics approach to evaluate the free energy profiles for ion transport. Near the selectivity filter region (P243 or P-2'), the free energy barrier for Na+ transport is over 4 kBT higher than Cl-, indicating anion selectivity of the channel. Furthermore, three layers of positivity charged rings in the extracellular domain also contribute to charge selectivity and facilitate Cl- permeability over Na+. Collectively, the charge selectivity of GluCl may be determined by overall electrostatic and ion dehydration effects, perhaps not deriving from a single region of the channel (the selectivity filter region near the intracellular entrance).
No preview · Article · Oct 2012 · The Journal of Physical Chemistry B
[Show abstract][Hide abstract] ABSTRACT: Control of the morphologies of polymer films and layers by addition of nanosize particles is a novel technique for design of nanomaterials and is also at the core of some important biological processes. In order to facilitate the analysis of experimental data and enable predictive engineering of such systems, solid theoretical understanding is necessary. We study theoretically and computationally the behavior of plane-grafted polymer layers (brushes) in athermal solvent, decorated with small nanoparticle inclusions, using mean field theory and coarse-grained simulations. We show that the morphology of such layers is very sensitive to the interaction between the polymers and the nanoparticles and to the nanoparticle density. In particular, the mean field model shows that for a certain range of parameters, the nanoparticles induce a sharp transition in the layer height, accompanied by a sharp increase in the number of adsorbed nanoparticles. At other parameter values, the layer height depends smoothly on the nanoparticle concentration. Predictions of the theoretical model are verified by Langevin dynamics simulations. The results of the paper are in qualitative agreement with experiments on in vitro models of biological transport and suggest strategies for morphological control of nanocomposite materials.
No preview · Article · Sep 2012 · Physical Review E
[Show abstract][Hide abstract] ABSTRACT: Langevin dynamics is used to compute the time evolution of the nonequilibrium motion of the atomic coordinates of a protein in response to ligand dissociation. The protein potential energy surface (PES) is approximated by a harmonic basin about the minimum of the unliganded state. Upon ligand dissociation, the protein undergoes relaxation from the bound to the unbound state. A coarse graining scheme based on rotation translation blocks (RTB) is applied to the relaxation of the two domain iron transport protein, ferric binding protein. This scheme provides a natural and efficient way to freeze out the small amplitude, high frequency motions within each rigid fragment, thereby allowing for the number of dynamical degrees of freedom to be reduced. The results obtained from all flexible atom (constraint free) dynamics are compared to those obtained using RTB-Langevin dynamics. To assess the impact of the assumed rigid fragment clustering on the temporal relaxation dynamics of the protein molecule, three distinct rigid block decompositions were generated and their responses compared. Each of the decompositions was a variant of the one-block-per-residue grouping, with their force and friction matrices being derived from their fully flexible counterpart. Monitoring the time evolution of the distance separating a selected pair of amino acids, the response curves of the blocked decompositions were similar in shape to each other and to the control system in which all atomic degrees of freedom are fully independent. The similar shape of the blocked responses showed that the variations in grouping had only a minor impact on the kinematics. Compared with the all atom responses, however, the blocked responses were faster as a result of the instantaneous transmission of force throughout each rigid block. This occurred because rigid blocking does not permit any intrablock deformation that could store or divert energy. It was found, however, that this accelerated response could be successfully corrected by scaling each eigenvalue in the appropriate propagation matrix by the least-squares fitted slope of the blocked vs nonblocked eigenvalue spectra. The RTB responses for each test system were dominated by small eigenvalue overdamped Langevin modes. The large eigenvalue members of each response dissipated within the first 5 ps, after which the long time response was dominated by a modest set of low energy, overdamped normal modes, that were characterized by highly cooperative, functionally relevant displacements. The response assuming that the system is in the overdamped limit was compared to the full phase space Langevin dynamics results. The responses after the first 5 ps were nearly identical, confirming that the inertial components were significant only in the initial stages of the relaxation. Since the propagator matrix in the overdamped formulation is real-symmetric and does not require the inertial component in the propagator, the computation time and memory footprint was reduced by 1 order of magnitude.
No preview · Article · Aug 2012 · The Journal of Physical Chemistry B
[Show abstract][Hide abstract] ABSTRACT: Early crystal structures of prokaryotic CLC proteins identified three Cl(-) binding sites: internal (S(int)), central (S(cen)), and external (S(ext)). A conserved external GLU (GLU(ex)) residue acts as a gate competing for S(ext). Recently, the first crystal structure of a eukaryotic transporter, CmCLC, revealed that in this transporter GLU(ex) competes instead for S(cen). Here, we use molecular dynamics simulations to investigate Cl(-) transport through CmCLC. The gating and Cl(-)/H(+) transport cycle are inferred through comparative molecular dynamics simulations with protonated and deprotonated GLU(ex) in the presence/absence of external potentials. Adaptive biasing force calculations are employed to estimate the potential of mean force profiles associated with transport of a Cl(-) ion from S(ext) to S(int), depending on the Cl(-) occupancy of other sites. Our simulations demonstrate that protonation of GLU(ex) is essential for Cl(-) transport from S(ext) to S(cen). The S(cen) site may be occupied by two Cl(-) ions simultaneously due to a high energy barrier (∼8 Kcal/mol) for a single Cl(-) ion to translocate from S(cen) to S(int). Binding two Cl(-) ions to S(cen) induces a continuous water wire from S(cen) to the extracellular solution through the side chain of the GLU(ex) gate. This may initiate deprotonation of GLU(ex), which then drives the two Cl(-) ions out of S(cen) toward the intracellular side via two putative Cl(-) transport paths. Finally, a conformational cycle is proposed that would account for the exchange stoichiometry.
Preview · Article · Mar 2012 · Biophysical Journal
[Show abstract][Hide abstract] ABSTRACT: Nuclear Pore Complex (NPC) is a biological ``nano-machine'' that
controls the macromolecular transport between the cell nucleus and the
cytoplasm. NPC functions without direct input of metabolic energy and
without transitions of the gate from a ``closed'' to an ``open'' state
during transport. The key and unique aspect of transport is the
interaction of the transported molecules with the unfolded, natively
unstructured proteins that cover the lumen of the NPC. Recently, the NPC
inspired creation of artificial bio-mimetic for nano-technology
applications. Although several models have been proposed, it is still
not clear how the passage of the transport factors is coupled to the
conformational dynamics of the unfolded proteins within the NPC.
Morphology changes in assemblies of the unfolded proteins induced by the
transport factors have been investigated experimentally in vitro. I will
present a coarse-grained theoretical and simulation framework that
mimics the interactions of unfolded proteins with nano-sized transport
factors. The simple physical model predicts morphology changes that
explain the recent puzzling experimental results and suggests possible
new modes of transport through the NPC. It also provides insights into
the physics of the behavior of unfolded proteins.
Preview · Article · Jan 2012 · Biophysical Journal
[Show abstract][Hide abstract] ABSTRACT: Mixtures of nanoparticles and polymer-like objects are encountered in many
nanotechnological applications and biological systems. We study the behavior of
grafted polymer layers decorated by nanoparticles that are attracted to the
polymers using lattice gas based mean field theory and accompanying
coarse-grained Brownian dynamics simulations. We find that the presence of
nanoparticles can induce large morphological transitions in the layer
morphology. In particular, at moderate nanoparticle concentrations, the
nanoparticles cause a reduction in the height of the polymer layer above the
grafting surface, which occurs via a novel first-order phase transition for
sufficiently strong attraction between the polymers and the nanoparticles and
smoothly for weak attractions. The predictions of the theory qualitatively
agree with the observed behavior of grafted natively unfolded protein strands
upon binding of proteins. The results also inform ways of designing nanopolymer
[Show abstract][Hide abstract] ABSTRACT: Analytical estimation of state-to-state rate constants is carried out for a recently developed discrete state model of chloride ion motion in a CLC chloride channel (Coalson and Cheng, J. Phys. Chem. B 2010, 114, 1424). In the original presentation of this model, the same rate constants were evaluated via three-dimensional Brownian dynamics simulations. The underlying dynamical theory is an appropriate single- or multiparticle three-dimensional Smoluchowski equation. Taking advantage of approximate geometric symmetries (based on the details of the model channel geometry), well-known formulas for state-to-state transition rates are appealed to herein and adapted as necessary to the problem at hand. Rates of ionic influx from a bulk electrolyte reservoir to the nearest binding site within the channel pore are particularly challenging to compute analytically because they reflect multi-ion interactions (as opposed to single-ion dynamics). A simple empirical correction factor is added to the single-ion rate constant formula in this case to account for the saturation of influx rate constants with increasing bulk Cl(-) concentration. Overall, the agreement between all analytically estimated rate constants is within a factor of 2 of those computed via three-dimensional Brownian dynamics simulations, and often better than this. Current-concentration curves obtained using rate constants derived from these two different computational approaches agree to within 25%.
No preview · Article · Jun 2011 · The Journal of Physical Chemistry A
[Show abstract][Hide abstract] ABSTRACT: Claudins form paracellular pores at the tight junction in epithelial cells. Profound depletion of extracellular calcium is well known to cause loosening of the tight junction with loss of transepithelial resistance. However, moderate variations in calcium concentrations within the physiological range can also regulate transepithelial permeability. To investigate the underlying molecular mechanisms, we studied the effects of calcium on the permeability of claudin-2, expressed in an inducible MDCK I cell line. We found that in the physiological range, calcium acts as a reversible inhibitor of the total conductance and Na(+) permeability of claudin-2, without causing changes in tight junction structure. The effect of calcium is enhanced at low Na(+) concentrations, consistent with a competitive effect. Furthermore, mutation of an intrapore negatively charged binding site, Asp-65, to asparagine partially abrogated the inhibitory effect of calcium. This suggests that calcium competes with Na(+) for binding to Asp-65. Other polyvalent cations had similar effects, including La(3+), which caused severe and irreversible inhibition of conductance. Brownian dynamics simulations demonstrated that such inhibition can be explained if Asp-65 has a relatively high charge density, thus favoring binding of Ca(2+) over that of Na(+), reducing Ca(2+) permeation by inhibiting its dissociation from this site, and decreasing Na(+) conductance through repulsive electrostatic interaction with Ca(2+). These findings may explain why hypercalcemia inhibits Na(+) reabsorption in the proximal tubule of the kidney.
No preview · Article · Nov 2010 · Journal of Biological Chemistry
[Show abstract][Hide abstract] ABSTRACT: Bacterial Gloeobacter violaceus pentameric ligand-gated ion channel (GLIC) is activated to cation permeation upon lowering the solution pH. Its function can be modulated by anesthetic halothane. In the present work, we integrate molecular dynamics (MD) and Brownian dynamics (BD) simulations to elucidate the ion conduction, charge selectivity, and halothane modulation mechanisms in GLIC, based on recently resolved X-ray crystal structures of the open-channel GLIC. MD calculations of the potential of mean force (PMF) for a Na(+) revealed two energy barriers in the extracellular domain (R109 and K38) and at the hydrophobic gate of transmembrane domain (I233), respectively. An energy well for Na(+) was near the intracellular entrance: the depth of this energy well was modulated strongly by the protonation state of E222. The energy barrier for Cl(-) was found to be 3-4 times higher than that for Na(+). Ion permeation characteristics were determined through BD simulations using a hybrid MD/continuum electrostatics approach to evaluate the energy profiles governing the ion movement. The resultant channel conductance and a near-zero permeability ratio (P(Cl)/P(Na)) were comparable to experimental data. On the basis of these calculations, we suggest that a ring of five E222 residues may act as an electrostatic gate. In addition, the hydrophobic gate region may play a role in charge selectivity due to a higher dehydration energy barrier for Cl(-) ions. The effect of halothane on the Na(+) PMF was also evaluated. Halothane was found to perturb salt bridges in GLIC that may be crucial for channel gating and open-channel stability, but had no significant impact on the single ion PMF profiles.
Full-text · Article · Oct 2010 · Journal of the American Chemical Society