CiteULike: Group: baker-group - library [6165 articles]

A stringent test of the cavity concept in continuum dielectrics

Arno Papazyan — 2008-07-24T11:44:00-00:00

The Journal of Chemical Physics, Vol. 107, No. 19. (1997), pp. 7975-7978.

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Continuum and Dipole-Lattice Models of Solvation

A Papazyan — 2008-07-24T11:42:55-00:00

J. Phys. Chem. B, Vol. 101, No. 51. (18 December 1997), pp. 11254-11264.

Abstract: Dipole-lattice and continuum-dielectric models, which are two important "simplified" models of solvation, are analyzed and compared. The conceptual basis of each approach is briefly examined, and the relationship between the two methodologies is explored. The importance of dipole lattices in the development of dielectric theory is stressed. The Clausius-Mossotti equation, which is the result of early attempts at relating the dielectric constant to "microscopic" quantities, also applies to cubic lattices of Langevin dipoles or point polarizabilities. The presence of thermal fluctuations, rather than inter-dipolar or specific short range interactions is found to be the fundamental reason for the deviation of dipolar materials from the Clausius-Mossotti equation. The fact that the continuum dielectric is the infinite dipole density limit of a more general dipole-lattice description is shown by recovering the continuum results with dipole lattices of high number density. The linearity of a continuum model is shown to be a direct consequence of being the infinite density limit of a dipole lattice. Finally, it is shown that the discreteness involved in the numerical solution of the Poisson equation cannot capture the effect of the physical discreteness in dipole lattices.

Effect of Solvent Discreteness on Solvation

A Papazyan — 2008-07-24T11:41:25-00:00

J. Phys. Chem. B, Vol. 102, No. 27. (2 July 1998), pp. 5348-5357.

Abstract: Solvent discreteness or "graininess" is usually considered to affect solvation energetics by modifying the intermolecular structure of the solvent, which in turn modifies its dielectric constant and the solute-solvent configurations. In this work, we separate the effect of solvent discreteness from solvent structure and polarity, as well as the arrangement of solvent particles around the solute. Because it is rather diffficult to do this separation with real solutions and their "realistic" models, we utilized translationally fixed dipole lattices, which allow such a separation. The polarity and the dielectric constant of a dipole lattice can be kept invariant as the number density of the dipoles is varied. The lattice spacing represents the degree of discreteness or coarseness in a lattice. Dipole lattices that polarize according to the continuum prediction, as well as truly interacting dipole lattices, lead to effective cavity sizes that are significantly smaller than the geometrically defined exclusion radius (the radius of a sphere around the center of a solute ion into which solvent particles cannot penetrate). The results are similar for lattices of opposite microscopic polarization tendencies and opposite ferroelectric divergence properties. Placing the solute in an interstitial or substitutional position does not cause a qualitative change in the results; increased solvent discreteness leads to smaller Born radii. To check whether this interesting result is peculiar to dipole lattice representations, we studied various forms of solute-solvent distribution function g(r). We derived a formula that connects g(r) to an effective cavity radius, with the approximation that the microscopic polarization follows the continuum prediction. The effective cavity radius is again found to be smaller than the exclusion radius. In agreement with the dipole-lattice analysis, the effective cavity radius decreases with increasing "graininess" of the solute-solvent pair distribution function; wavier g(r)'s lead to smaller effective cavity sizes. This result has important conceptual and practical implications in solvation modeling. Solvent discreteness becomes an important factor in solvation in its own right, distinct from its indirect effects felt through modified solvent properties and solute-solvent configurations. Also, in light of the present results, it should be possible to develop better parameterization schemes for simplified solvation models.

Factor Va Alters the Conformation of the Na+-Binding Loop of Factor Xa in the Prothrombinase Complex

Likui Yang — 2008-07-24T11:13:52-00:00

Biochemistry, Vol. 47, No. 22. (3 June 2008), pp. 5976-5985.

Abstract: Structural and mutagenesis data have indicated that the 220-loop of thrombin is stabilized by a salt-bridge between Glu-217 and Lys-224, thereby facilitating the octahedral coordination of Na+ with contributions from two carbonyl O atoms of Arg-221a and Lys-224. All three residues are also conserved in fXa and the X-ray crystal structure of fXa indicates that both Glu-217 and Lys-224 are within hydrogen-bonding distance from one another. To investigate the role of these three residues in the catalytic function of fXa and their contribution to interaction with Na+, we substituted them with Ala and characterized their properties in both amidolytic and proteolytic activity assays. The results indicate that the affinity of all three mutants for interaction with Na+ has been impaired. The mutant with the greatest loss of affinity for Na+ (E217A or E217Q) also exhibited a dramatic impairment (~34 orders of magnitude) in its activity toward both synthetic and natural substrates. Interestingly, factor Va (fVa) restored most of the catalytic defect with prothrombin, but not with the synthetic substrate. Both Glu-217 mutants exhibited a near normal affinity for fVa in the prothrombinase assay, but a markedly lower affinity for the cofactor in a direct-binding assay. These results suggest that, similar to thrombin, an ionic interaction between Glu-217 and Lys-224 stabilizes the 220-loop of fXa for binding Na+. They further support the hypothesis that the Na+ and fVa-binding sites of fXa are energetically linked and that a cofactor function for fVa in the prothrombinase complex involves inducing a conformational change in the 220-loop of fXa that appears to stabilize this loop in the Na+-bound active conformation.

Modest stabilization by most hydrogen-bonded side-chain interactions in membrane proteins

Nathan Joh — 2008-05-26T13:58:20-00:00

Nature (25 May 2008)

Structural analysis of the essential self-cleaving type III secretion proteins EscU and SpaS

Raz Zarivach — 2008-04-30T19:31:59-00:00

Nature, Vol. 453, No. 7191., pp. 124-127.

Lipid bilayer structure determined by the simultaneous analysis of neutron and x-ray scattering data

Norbert Kucerka — 2008-05-25T00:55:10-00:00

Biophys. J. (23 May 2008), biophysj.108.132662.

Quantitative structures were obtained for the fully hydrated fluid phases of dioleoyl-phosphatidylcholine (DOPC) and dipalmitoyl-phosphatidylcholine (DPPC) bilayers by simultaneously analyzing x-ray and neutron scattering data. The neutron data for DOPC included two solvent contrasts, 50% and 100% D2O. For DPPC additional contrast data were obtained with deuterated analogues DPPC_d62, DPPC_d13 and DPPC_d9. For the analysis we developed a model that is based on volume probability distributions and their spatial conservation. The model's design was guided and tested by a DOPC molecular dynamics simulation. The model consistently captures the salient features found in both electron and neutron scattering density profiles (SDP). A key result of the analysis is the molecular surface area, A. For DPPC at 50 degreesC A=63.0 A2 while for DOPC at 30 degreesC A=67.4 A2, with estimated uncertainties of 1 A2. Although A for DPPC agrees with a recently reported value obtained solely from the analysis of x-ray scattering data, A for DOPC is almost 10 % smaller. This improved method for determining lipid areas helps to reconcile long standing differences in the values of lipid areas obtained from stand alone x-ray and neutron scattering experiments, and poses new challenges for molecular dynamics simulations. 10.1529/biophysj.108.132662

Membrane nanotubes: dynamic long-distance connections between animal cells

Daniel Davis — 2008-05-23T14:16:01-00:00

Nature Reviews Molecular Cell Biology, Vol. 9, No. 6. (23 April 2008), pp. 431-436.

A meshless, spectrally accurate, integral equation solver for molecular surface electrostatics

Shih-Hsien Kuo — 2008-07-24T10:44:31-00:00

J. Emerg. Technol. Comput. Syst., Vol. 4, No. 2. (April 2008), pp. 1-30.

Cholesterol Packing around Lipids with Saturated and Unsaturated Chains: A Simulation Study

Sagar Pandit — 2008-06-04T00:50:32-00:00

Langmuir (3 June 2008)

Abstract: The fundamental role of cholesterol in the regulation of eukaryotic membrane structure is well-established. However the manner in which atomic level interactions between cholesterol and lipids, with varying degrees of chain unsaturation and polar groups, affect the overall structure and organization of the bilayer is only beginning to be understood. In this paper we describe a series of Molecular Dynamics simulations designed to provide new insights into lipidcholesterol interactions as a function of chain unsaturation. We have run simulations of varying concentrations of cholesterol in dipalmitoyl phosphatidylcholine (DPPC), palmitoyl-oleyol phosphatidylcholine (POPC), and dioleyol phosphatidylcholine (DOPC) bilayers. Structural analysis of the simulations reveals both atomistic and systemic details of the interactions and are presented here. In particular, we find that the minimum partial molecular area of cholesterol occurs in POPCChol mixtures implying the most favorable packing. Physically, this appears to be related to the fact that the two faces of the cholesterol molecule are different from each other and that the steric cross section of cholesterol molecules drops sharply near the small chain tails.

Computational Insights on the Competing Effects of Nitric Oxide in Regulating Apoptosis

Elife Bagci — 2008-07-23T11:10:59-00:00

PLoS ONE, Vol. 3, No. 5. (28 May 2008), e2249.

Despite the establishment of the important role of nitric oxide (NO) on apoptosis, a molecular- level understanding of the origin of its dichotomous pro- and anti-apoptotic effects has been elusive. We propose a new mathematical model for simulating the effects of nitric oxide (NO) on apoptosis. The new model integrates mitochondria-dependent apoptotic pathways with NO-related reactions, to gain insights into the regulatory effect of the reactive NO species N2O3, non-heme iron nitrosyl species (FeLnNO), and peroxynitrite (ONOO−). The biochemical pathways of apoptosis coupled with NO-related reactions are described by ordinary differential equations using mass-action kinetics. In the absence of NO, the model predicts either cell survival or apoptosis (a bistable behavior) with shifts in the onset time of apoptotic response depending on the strength of extracellular stimuli. Computations demonstrate that the relative concentrations of anti- and pro-apoptotic reactive NO species, and their interplay with glutathione, determine the net anti- or pro-apoptotic effects at long time points. Interestingly, transient effects on apoptosis are also observed in these simulations, the duration of which may reach up to hours, despite the eventual convergence to an anti-apoptotic state. Our computations point to the importance of precise timing of NO production and external stimulation in determining the eventual pro- or anti-apoptotic role of NO.

Harmonic averaging of smooth permittivity functions in finite-difference PoissonBoltzmann Electrostatics

Kottmann — 2008-05-12T21:59:15-00:00

Theoretical Chemistry Accounts, Vol. 119, No. 5-6. (April 2008), pp. 421-427.

Free-energy analysis of the molecular binding into lipid membrane with the method of energy representation

Nobuyuki Matubayasi — 2008-05-22T23:34:42-00:00

The Journal of Chemical Physics, Vol. 128, No. 19. (2008)

Regulated Protein Denitrosylation by Cytosolic and Mitochondrial Thioredoxins

Moran Benhar — 2008-07-23T10:55:28-00:00

Science, Vol. 320, No. 5879. (23 May 2008), pp. 1050-1054.

Nitric oxide acts substantially in cellular signal transduction through stimulus-coupled S-nitrosylation of cysteine residues. The mechanisms that might subserve protein denitrosylation in cellular signaling remain uncharacterized. Our search for denitrosylase activities focused on caspase-3, an exemplar of stimulus-dependent denitrosylation, and identified thioredoxin and thioredoxin reductase in a biochemical screen. In resting human lymphocytes, thioredoxin-1 actively denitrosylated cytosolic caspase-3 and thereby maintained a low steady-state amount of S-nitrosylation. Upon stimulation of Fas, thioredoxin-2 mediated denitrosylation of mitochondria-associated caspase-3, a process required for caspase-3 activation, and promoted apoptosis. Inhibition of thioredoxin-thioredoxin reductases enabled identification of additional substrates subject to endogenous S-nitrosylation. Thus, specific enzymatic mechanisms may regulate basal and stimulus-induced denitrosylation in mammalian cells. 10.1126/science.1158265

BIOCHEMISTRY: SNO Removal

Arne Holmgren — 2008-07-23T10:54:52-00:00

Science, Vol. 320, No. 5879. (23 May 2008), pp. 1019-1020.

10.1126/science.1159246

Fluorescence Imaging of Membrane Dynamics

Jay Groves — 2008-07-23T06:12:41-00:00

Annual Review of Biomedical Engineering, Vol. 10, No. 1. (2008), pp. 311-338.

Imaging membrane dynamics is an important goal, motivated by the abundance of biochemical and biophysical events that are orchestrated at, or by, cellular membranes. The short length scales, fast timescales, and environmental requirements of membrane phenomena present challenges to imaging experiments. Several technical advances offer means to overcome these challenges, and we describe here three powerful techniques applicable to membrane imaging: total internal reflection fluorescence (TIRF) microscopy, fluorescence interference contrast (FLIC) microscopy, and fluorescence correlation spectroscopy (FCS). For each, we discuss the physics underpinning the approach, its practical implementation, and recent examples highlighting its achievements in exploring the membrane environment.

Ontology-based knowledge representation for bioinformatics

Robert Stevens — 2007-01-18T23:26:27-00:00

Brief Bioinform, Vol. 1, No. 4. (1 January 2000), pp. 398-414.

Much of biology works by applying prior knowledge ( what is known') to an unknown entity, rather than the application of a set of axioms that will elicit knowledge. In addition, the complex biological data stored in bioinformatics databases often require the addition of knowledge to specify and constrain the values held in that database. One way of capturing knowledge within bioinformatics applications and databases is the use of ontologies. An ontology is the concrete form of a conceptualisation of a community's knowledge of a domain This paper aims to introduce the reader to the use of ontologies within bioinformatics. A description of the type of knowledge held in an ontology will be given. the paper will be illustrated throughout with examples taken from bioinformatics and molecular biology, and a survey of current biological ontologies will be presented. From this it will be seen that the use to which the ontology is put largely determines the content of the ontology. Finally, the paper will describe the process of building an ontology, introducing the reader to the techniques and methods currently in use and the open research questions in ontology development. 10.1093/bib/1.4.398

Where are the semantics in the semantic web?

Michael Uschold — 2005-06-07T22:46:37-00:00

AI Mag., Vol. 24, No. 3. (September 2003), pp. 25-36.

Dimensions of knowledge sharing and reuse

Mark Musen — 2008-07-22T11:39:35-00:00

Computers and Biomedical Research, Vol. 25, No. 5. (October 1992), pp. 435-467.

Many workers in medical informatics are seeking to reuse knowledge in new applications and to share encoded knowledge across software environments. Knowledge reuse involves many dimensions, including the reapplication of lexicons, ontologies, inference syntax, tasks, and problem-solving methods. Principal obstacles to all current work in knowledge sharing involve the difficulties of achieving consensus regarding what knowledge representations mean, of enumerating the context features and background knowledge required to ascribe meaning to a particular knowledge representation, and of describing knowledge independent of specific interpreters or inference engines. Progress in the area of knowledge sharing will necessitate more practical experience with attempts to interchange knowledge as well as better tools for viewing and editing knowledge representations at appropriate levels of abstraction. The PROTÉGÉ-II project is one attempt to provide a knowledge-base authoring environment in which developers can experiment with the reuse of knowledge-level problemsolving methods, task models, and domain ontologies.

Overview and utilization of the NCI Thesaurus

Fragoso Gilberto — 2005-03-08T10:41:29-00:00

Comparative and Functional Genomics, Vol. 5, No. 8. (December 2004), pp. 648-654.

Sequence Ontology annotation guide: Conference Papers

Karen Eilbeck — 2007-10-04T18:08:44-00:00

Comp. Funct. Genomics, Vol. 5, No. 8. (December 2004), pp. 642-647.

Statistical mechanics of polar fluids in electric fields

Ho Ye — 2008-07-22T11:00:30-00:00

The Journal of Chemical Physics, Vol. 72, No. 3. (1980), pp. 1597-1613.

Mastering Your Ph.D.: A Career in Management Consulting

2008-07-22T10:51:30-00:00

Science Careers (2008)

Problem-solving and communication are important skills if you want to advise industry executives.

Very fast prediction and rationalization of pKa values for protein-ligand complexes

Delphine Bas — 2008-06-24T12:44:20-00:00

Proteins: Structure, Function, and Bioinformatics, Vol. 9999, No. 9999. (2008), NA.

The PROPKA method for the prediction of the pKa values of ionizable residues in proteins is extended to include the effect of non-proteinaceous ligands on protein pKa values as well as predict the change in pKa values of ionizable groups on the ligand itself. This new version of PROPKA (PROPKA 2.0) is, as much as possible, developed by adapting the empirical rules underlying PROPKA 1.0 to ligand functional groups. Thus, the speed of PROPKA is retained, so that the pKa values of all ionizable groups are computed in a matter of seconds for most proteins. This adaptation is validated by comparing PROPKA 2.0 predictions to experimental data for 26 protein-ligand complexes including trypsin, thrombin, three pepsins, HIV-1 protease, chymotrypsin, xylanase, hydroxynitrile lyase, and dihydrofolate reductase. For trypsin and thrombin, large protonation state changes (|n| > 0.5) have been observed experimentally for 4 out of 14 ligand complexes. PROPKA 2.0 and Klebe's PEOE approach (Czodrowski P et al. J Mol Biol 2007;367:1347-1356) both identify three of the four large protonation state changes. The protonation state changes due to plasmepsin II, cathepsin D and endothiapepsin binding to pepstatin are predicted to within 0.4 proton units at pH 6.5 and 7.0, respectively. The PROPKA 2.0 results indicate that structural changes due to ligand binding contribute significantly to the proton uptake/release, as do residues far away from the binding site, primarily due to the change in the local environment of a particular residue and hence the change in the local hydrogen bonding network. Overall the results suggest that PROPKA 2.0 provides a good description of the protein-ligand interactions that have an important effect on the pKa values of titratable groups, thereby permitting fast and accurate determination of the protonation states of key residues and ligand functional groups within the binding or active site of a protein. Proteins 2008. © 2008 Wiley-Liss, Inc.

Hydrodynamic modeling of diffusion tensor properties of flexible molecules

Vincenzo Barone — 2008-07-22T10:43:04-00:00

Journal of Computational Chemistry, Vol. 9999, No. 9999. (2008), NA.

We present a computationally efficient implementation of hydrodynamic modeling for the evaluation of diffusion tensors of molecules with internal degrees of freedom, adapted to take into account information from linear scaling computations of solvent accessible surfaces implemented in the framework of last generation continuum solvent models. Torsional angles are taken also explicitly into account, while retaining correct hydrodynamic interactions. A comparison with literature data is presented to prove the effectiveness of the approach for a wide range of molecular dimensions and solvent environments. © 2008 Wiley Periodicals, Inc. J Comput Chem, 2008

Test of the Gouy-Chapman Theory for a Charged Lipid Membrane against Explicit-Solvent Molecular Dynamics Simulations

Myunggi Yi — 2008-07-21T20:02:20-00:00

Physical Review Letters, Vol. 101, No. 3. (2008)

A wealth of experimental data has verified the applicability of the Gouy-Chapman (GC) theory to charged lipid membranes. Surprisingly, a validation of GC by molecular dynamics (MD) simulations has been elusive. Here, we report a test of GC against extensive MD simulations of an anionic lipid bilayer solvated by water at different concentrations of NaCl or KCl. We demonstrate that the ion distributions from the simulations agree remarkably well with GC predictions when information on the adsorption of counterions to the bilayer is incorporated.

Ion Specific Protein Assembly and Hydrophobic Surface Forces

Mikael Lund — 2008-06-26T17:23:40-00:00

Physical Review Letters, Vol. 100, No. 25. (2008)

Large anions are attracted to hydrophobic surfaces while smaller, well solvated ions are repelled. Using a combination of explicit solvent and continuum model simulations we show that this leads to significant ion-specific protein-protein interactions due to hydrophobic patches on the protein surfaces. In solutions of NaI and NaCl we calculate the potentials of mean force and find that the resulting second virial coefficients for lysozyme correspond well with experiment. We argue that ionic interactions with nonpolar surface groups may play an important role for biomolecular assembly and Hofmeister-type effects.

Robustly Estimating the Flow Direction of Information in Complex Physical Systems

Guido Nolte — 2008-06-26T00:26:34-00:00

Physical Review Letters, Vol. 100, No. 23. (2008)

We propose a new measure (phase-slope index) to estimate the direction of information flux in multivariate time series. This measure (a) is insensitive to mixtures of independent sources, (b) gives meaningful results even if the phase spectrum is not linear, and (c) properly weights contributions from different frequencies. These properties are shown in extended simulations and contrasted to Granger causality which yields highly significant false detections for mixtures of independent sources. An application to electroencephalography data (eyes-closed condition) reveals a clear front-to-back information flow.

Theory of Dielectric Relaxation in Polar Liquids

Tsu Nee — 2008-07-17T21:38:56-00:00

The Journal of Chemical Physics, Vol. 52, No. 12. (1970), pp. 6353-6363.

Electric Moments of Molecules in Liquids

L Onsager — 2008-07-17T17:31:49-00:00

Journal of the American Chemical Society, Vol. 58, No. 8. (1936), pp. 1486-1493.

The Geometry Behind Numerical Solvers of the Poisson-Boltzmann Equation

X Shi — 2008-07-16T15:22:01-00:00

Communications in Computational Physics, Vol. 3 (2008), pp. 1032-1050.

Electrostatics interactions play a major role in the stabilization of biomolecules: as such, they remain a major focus of theoretical and computational studies in biophysics. Electrostatics in solution is strongly dependent on the nature of the solvent and on the ions it contains. While methods that treat the solvent and ions explicitly provide an accurate estimate of these interactions, they are usually computationally too demanding to study large macromolecular systems. Implicit solvent methods provide a viable alternative, especially those based on Poisson theory. The Poisson-Boltzmann equation (PBE) treats the system in a mean field approximation, providing reasonable estimates of electrostatics interactions in a solvent treated as continuum. In the first part of this paper, we review the theory behind the PBE, including recent improvement in which ions size and dipolar features of solvent molecules are taken into account explicitly. The PBE is a non linear second order differential equation with discontinuous coefficients, for which no analytical solution is available for large molecular systems. Many numerical solvers have been developed that solve a discretized version of the PBE on a mesh, either using finite difference, finite element, or boundary element methods. The accuracy of the solutions provided by these solvers highly depend on the geometry of their underlying meshes, as well as on the method used to embed the physical system on the mesh. In the second part of the paper, we describe a new geometric approach for generating unstructured tetrahedral meshes as well as simplifications of these meshes that are well fitted for solving the PBE equation using multigrid approaches.

Dipolar Poisson-Boltzmann Equation: Ions and Dipoles Close to Charge Interfaces

Ariel Abrashkin — 2007-12-27T04:31:09-00:00

Physical Review Letters, Vol. 99, No. 7. (2007)

We present an extension to the Poisson-Boltzmann model where the dipolar features of solvent molecules are taken explicitly into account. The formulation is derived at mean-field level and can be extended to any order in a systematic expansion. It is applied to a two-plate system with oppositely charged surfaces. The ion distribution and profiles in the dipolar order parameter are calculated and can result in a large correction to the interplate pressure.

Poisson-Boltzmann Theory for Membranes with Mobile Charged Lipids and the pH-Dependent Interaction of a DNA Molecule with a Membrane

Christian Fleck — 2008-03-19T16:40:37-00:00

Biophys. J., Vol. 82, No. 1. (1 January 2002), pp. 76-92.

We consider a planar stiff model membrane consisting of mobile surface groups whose state of charge depends on the pH and the ionic composition of the adjacent electrolyte solution. To calculate the mean-field interaction potential between a charged object and such a model membrane, one needs to solve a Poisson-Boltzmann boundary value problem. We here derive and discuss the boundary condition at the membrane surface, a condition that is generally appropriate for biological membranes where two charge-regulating mechanisms are present at the same time: the pH-dependent chemical charge regulation and a regulation through the in-plane mobility of the surface groups. As an application of this general formalism, we consider the specific example of a single DNA molecule, approximated by a cylinder with smeared-out surface charges, interacting with such a model membrane. We study the effect that the two competing charge-regulating mechanisms have on the DNA/membrane interaction and the distribution of surface ions in the plane of the membrane. We find that, at short DNA-membrane distances, membrane fluidity can have a considerable impact on the DNA adsorption behavior and can lead to such counterintuitive phenomena as the adsorption of a negatively charged DNA onto a (on average) negatively charged membrane.

Morphological transitions of vesicles induced by AC electric fields

Said Aranda — 2008-05-19T23:43:43-00:00

Biophys. J. (16 May 2008), biophysj.108.132548.

When subjected to alternating electric (AC) fields in the frequency range 102 - 108 Hz, giant lipid vesicles attain oblate, prolate and spherical shapes and undergo morphological transitions between these shapes as one varies the field frequency and/or the conductivities lambdain and lambdaex of the aqueous solution inside and outside the vesicles. Four different transitions are observed with characteristic frequencies that depend primarily on the conductivity ratio lambdain/lambdaex. The theoretical models that have been described in the literature are not able to describe all of these morphological transitions. 10.1529/biophysj.108.132548

The signaling pathway of rhodopsin.

Y Kong — 2007-07-27T16:17:22-00:00

Structure, Vol. 15, No. 5. (May 2007), pp. 611-623.

The signal-transduction mechanism of rhodopsin was studied by molecular dynamics (MD) simulations of the high-resolution, inactive structure in an explicit membrane environment. The simulations were employed to calculate equal-time correlations of the fluctuating interaction energy of residue pairs. The resulting interaction-correlation matrix was used to determine a network that couples retinal to the cytoplasmic interface, where transducin binds. Two highly conserved motifs, D(E)RY and NPxxY, were found to have strong interaction correlation with retinal. MD simulations with restraints on each transmembrane helix indicated that the major signal-transduction pathway involves the interdigitating side chains of helices VI and VII. The functional roles of specific residues were elucidated by the calculated effect of retinal isomerization from 11-cis to all-trans on the residue-residue interaction pattern. It is suggested that Glu134 may act as a "signal amplifier" and that Asp83 may introduce a threshold to prevent background noise from activating rhodopsin.

From the Cover: A dry ligand-binding cavity in a solvated protein

Johan Qvist — 2008-05-26T20:32:13-00:00

Proceedings of the National Academy of Sciences, Vol. 105, No. 17. (29 April 2008), pp. 6296-6301.

Ligands usually bind to proteins by displacing water from the binding site. The affinity and kinetics of binding therefore depend on the hydration characteristics of the site. Here, we show that the extreme case of a completely dehydrated free binding site is realized for the large nonpolar binding cavity in bovine -lactoglobulin. Because spatially delocalized water molecules may escape detection by x-ray diffraction, we use water 17O and 2H magnetic relaxation dispersion (MRD), 13C NMR spectroscopy, molecular dynamics simulations, and free energy calculations to establish the absence of water from the binding cavity. Whereas carbon nanotubes of the same diameter are filled by a hydrogen-bonded water chain, the MRD data show that the binding pore in the apo protein is either empty or contains water molecules with subnanosecond residence times. However, the latter possibility is ruled out by the computed hydration free energies, so we conclude that the 315 A3 binding pore is completely empty. The apo protein is thus poised for efficient binding of fatty acids and other nonpolar ligands. The qualitatively different hydration of the -lactoglobulin pore and carbon nanotubes is caused by subtle differences in water-wall interactions and water entropy. 10.1073/pnas.0709844105

Signaling pathways of PDZ2 domain: A molecular dynamics interaction correlation analysis

Y Kong — 2008-07-11T10:59:58-00:00

Proteins, Vol. in press

PDZ domains are found in many signaling proteins. One of their functions is to provide scaffolds for forming membrane-associated protein complexes by binding to the carboxyl termini of their partners. PDZ domains are thought also to play a signal transduction role by propagating the information that binding has occurred to remote sites. In this study, a molecular dynamics (MD) simulation-based approach, referred to as an interaction correlation analysis, is applied to the PDZ2 domain to identify the possible signal transduction pathways. A residue correlation matrix is constructed from the interaction energy correlations between all residue pairs obtained from the MD simulations. Two continuous interaction pathways, starting at the ligand binding pocket, are identified by a hierarchical clustering analysis of the residue correlation matrix. One pathway is mainly localized at the N-terminal side of helix 1 and the adjacent C-terminus of loop 1-2. The other pathway is perpendicular to the central -sheet and extends toward the side of PDZ2 domain opposite to the ligand binding pocket. The results complement previous studies based on multiple sequence analysis, NMR, and MD simulations. Importantly, they reveal the energetic origin of the long-range coupling. The PDZ2 results, as well as the earlier rhodopsin analysis, show that the interaction correlation analysis is a robust approach for determining pathways of intramolecular signal transduction. Proteins 2008. © 2008 Wiley-Liss, Inc.

Tortuosity and anomalous diffusion in the neuromuscular junction

Daniel Lacks — 2008-07-10T11:04:19-00:00

Physical Review E (Statistical, Nonlinear, and Soft Matter Physics), Vol. 77, No. 4. (2008)

The signal transfer from nerve to muscle occurs by diffusion across the neuromuscular junction. The continuum level analysis of diffusion processes is based on the diffusion equation, which in one dimension is c/t=D(2c/x2), where c is the molecular concentration and D is the diffusivity. However, in confined systems such as the neuromuscular junction, the diffusion equation may not be valid, and even if valid the value of D may be altered by the confinement. In this paper, Monte Carlo simulations are used to probe diffusion at the molecular level in a realistic model of a neuromuscular junction. The results show that diffusion is anomalous (i.e., not described by the diffusion equation) for time scales less than ~0.01 s, which is the time scale relevant for signaling processes in the synapse. At longer time scales, the diffusion is normal (i.e., described by the diffusion equation), but with a value of D that is reduced by a factor of ~5 times compared to the value for diffusion in open space. As the width of the synaptic cleft decreases, these effects become even more pronounced. The physical basis of these results is described in terms of the structure of the neuromuscular junction.

Annotation-Modules: A tool for finding significant combinations of multisource annotations for gene lists.

Michael Hackenberg — 2008-05-10T08:47:08-00:00

Bioinformatics (Oxford, England) (8 May 2008)

MOTIVATION: The ontological analysis of the gene lists obtained from DNA microarray experiments constitutes an important step in understanding the underlying biology of the analyzed system. Over the last years, many other high-throughput techniques emerged, covering now basically all "omics" fields. However, for some of these techniques the generally used functional ontologies might not be sufficient to describe the biological system represented by the derived gene lists. For a more complete and correct interpretation of these experiments, it is important to extend substantially the number of annotations, adapting the ontological analysis to the new emerging techniques. RESULTS: We developed Annotation-Modules, which offers an improvement over the current tools which improves the current tools in two critical aspects. Firstly, the underlying annotation database implements features from many different fields like gene regulation and expression, sequence properties, evolution and conservation, genomic localization and functional categories - resulting in about 60 different annotation features. Secondly, it examines not only single annotations but also all the combinations, which is important to gain insight into the interplay of different mechanisms in the analyzed biological system. AVAILABILITY: http://web.bioinformatics.cicbiogune.es/AM/AnnotationModules.php.

Dynameomics: a multi-dimensional analysis-optimized database for dynamic protein data

Catherine Kehl — 2008-07-10T10:58:07-00:00

Protein Engineering, Design and Selection, Vol. 21, No. 6. (1 June 2008), pp. 379-386.

The Dynameomics project is our effort to characterize the native-state dynamics and folding/unfolding pathways of representatives of all known protein folds by way of molecular dynamics simulations, as described by Beck et al. (in Protein Eng. Des. Select., the first paper in this series). The data produced by these simulations are highly multidimensional in structure and multi-terabytes in size. Both of these features present significant challenges for storage, retrieval and analysis. For optimal data modeling and flexibility, we needed a platform that supported both multidimensional indices and hierarchical relationships between related types of data and that could be integrated within our data warehouse, as described in the accompanying paper directly preceding this one. For these reasons, we have chosen On-line Analytical Processing (OLAP), a multi-dimensional analysis optimized database, as an analytical platform for these data. OLAP is a mature technology in the financial sector, but it has not been used extensively for scientific analysis. Our project is further more unusual for its focus on the multidimensional and analytical capabilities of OLAP rather than its aggregation capacities. The dimensional data model and hierarchies are very flexible. The query language is concise for complex analysis and rapid data retrieval. OLAP shows great promise for the dynamic protein analysis for bioengineering and biomedical applications. In addition, OLAP may have similar potential for other scientific and engineering applications involving large and complex datasets. 10.1093/protein/gzn015

Dynameomics: design of a computational lab workflow and scientific data repository for protein simulations

Andrew Simms — 2008-07-10T10:56:24-00:00

Protein Engineering, Design and Selection, Vol. 21, No. 6. (1 June 2008), pp. 369-377.

Dynameomics is a project to investigate and catalog the native-state dynamics and thermal unfolding pathways of representatives of all protein folds using solvated molecular dynamics simulations, as described in the preceding paper. Here we introduce the design of the molecular dynamics data warehouse, a scalable, reliable repository that houses simulation data that vastly simplifies management and access. In the succeeding paper, we describe the development of a complementary multidimensional database. A single protein unfolding or native-state simulation can take weeks to months to complete, and produces gigabytes of coordinate and analysis data. Mining information from over 3000 completed simulations is complicated and time-consuming. Even the simplest queries involve writing intricate programs that must be built from low-level file system access primitives and include significant logic to correctly locate and parse data of interest. As a result, programs to answer questions that require data from hundreds of simulations are very difficult to write. Thus, organization and access to simulation data have been major obstacles to the discovery of new knowledge in the Dynameomics project. This repository is used internally and is the foundation of the Dynameomics portal site http://www.dynameomics.org. By organizing simulation data into a scalable, manageable and accessible form, we can begin to address substantial questions that move us closer to solving biomedical and bioengineering problems. 10.1093/protein/gzn012

Dynameomics: mass annotation of protein dynamics and unfolding in water by high-throughput atomistic molecular dynamics simulations

David Beck — 2008-07-10T10:55:21-00:00

Protein Engineering, Design and Selection, Vol. 21, No. 6. (1 June 2008), pp. 353-368.

The goal of Dynameomics is to perform atomistic molecular dynamics (MD) simulations of representative proteins from all known folds in explicit water in their native state and along their thermal unfolding pathways. Here we present 188-fold representatives and their native state simulations and analyses. These 188 targets represent 67% of all the structures in the Protein Data Bank. The behavior of several specific targets is highlighted to illustrate general properties in the full dataset and to demonstrate the role of MD in understanding protein function and stability. As an example of what can be learned from mining the Dynameomics database, we identified a protein fold with heightened localized dynamics. In one member of this fold family, the motion affects the exposure of its phosphorylation site and acts as an entropy sink to offset another portion of the protein that is relatively immobile in order to present a consistent interface for protein docking. In another member of this family, a polymorphism in the highly mobile region leads to a host of disease phenotypes. We have constructed a web site to provide access to a novel hybrid relational/multidimensional database (described in the succeeding two papers) to view and interrogate simulations of the top 30 targets: http://www.dynameomics.org. The Dynameomics database, currently the largest collection of protein simulations and protein structures in the world, should also be useful for determining the rules governing protein folding and kinetic stability, which should aid in deciphering genomic information and for protein engineering and design. 10.1093/protein/gzn011

Cell Penetrating Peptides: How Do They Do It?

Henry Herce — 2008-07-09T10:39:55-00:00

Journal of Biological Physics

Abstract Cell penetrating peptides consist of short sequences of amino acids containing a large net positive charge that are able to penetrate almost any cell, carrying with them relatively large cargoes such as proteins, oligonucleotides, and drugs. During the 10 years since their discovery, the question of how they manage to translocate across the membrane has remained unanswered. The main discussion has been centered on whether they follow an energy-independent or an energy-dependent pathway. Recently, we have discovered the possibility of an energy-independent pathway that challenges fundamental concepts associated with protein-membrane interactions (Herce and Garcia, PNAS, 104: 20805 (2007) [1]). It involves the translocation of charged residues across the hydrophobic core of the membrane and the passive diffusion of these highly charged peptides across the membrane through the formation of aqueous toroidal pores. The aim of this review is to discuss the details of the mechanism and interpret some experimental results consistent with this view.

United-Atom Acyl Chains for CHARMM Phospholipids

Jérôme Hénin — 2008-06-09T21:30:28-00:00

J. Phys. Chem. B, Vol. 112, No. 23. (12 June 2008), pp. 7008-7015.

Abstract: In all-atom simulations of lipid membranes, explicit hydrogen atoms contained in the hydrocarbon region are described by a large number of degrees of freedom, although they convey only limited physical information. We propose an implicit-hydrogen model for saturated and monounsaturated acyl chains, aimed at complementing the all-atom CHARMM27 model for phospholipid headgroups. Torsional potentials and nonbonded parameters were fitted to reproduce experimental data and free energy surfaces of all-atom model systems. Comparative simulations of fluid-phase POPC bilayers were performed using the all-hydrogen force field and the present model. The hybrid model accelerates a typical bilayer simulation by about 50% while sacrificing a minimal amount of detail with respect to the fully atomistic description. In addition, the united-atom description is energetically compatible with all-atom CHARMM models, making it suitable for simulations of complex membrane systems.

Role of Backbone−Solvent Interactions in Determining Conformational Equilibria of Intrinsically Disordered Proteins

Hoang Tran — 2008-05-22T00:53:03-00:00

J. Am. Chem. Soc. (16 May 2008)

Abstract: Intrinsically disordered proteins (IDPs) are functional proteins that do not fold into well-defined three-dimensional structures under physiological conditions. IDP sequences have low hydrophobicity, and hence, recent experiments have focused on quantitative studies of conformational ensembles of archetypal IDP sequences such as polyglutamine and glycine-serine block copolypeptides. Results from these experiments show that, despite the absence of hydrophobic residues, polar IDPs prefer ensembles of collapsed structures in aqueous milieus. Do these preferences originate in interactions that are unique to polar sidechains? The current study addresses this issue by analyzing conformational equilibria for polyglycine and a glycine-serine block copolypeptide in two environments, namely, water and 8 M urea. Polyglycine, a poly secondary-amide, has no sidechains and is a useful model system for generic polypeptide backbones. Results based on large-scale molecular dynamics simulations show that polyglycine forms compact, albeit disordered, globules in water and swollen, disordered coils in 8 M urea. There is minimal overlap between conformational ensembles in the two environments. Analysis of order parameters derived from theories for flexible polymers show that water at ambient temperatures is a poor solvent for generic polypeptide backbones. Therefore, the experimentally observed preferences for polyglutamine and glycine-serine block copolypeptides must originate, at least partially, in polypeptide backbones. A preliminary analysis of the driving forces that lead to distinct conformational preferences for polyglycine in two different environments is presented. Implications for describing conformational ensembles of generic IDP sequences are also discussed.

Dielectric relaxation in proteins: the computational perspective.

Thomas Simonson — 2008-05-12T17:20:19-00:00

Photosynthesis research (29 April 2008)

In photoexcitation and electron transfer, a new dipole or charge is introduced, and the structure is adjusted. This adjustment represents dielectric relaxation, which is the focus of this review. We concentrate on a few selected topics. We discuss linear response theory, as a unifying framework and a tool to describe non-equilibrium states. We review recent, molecular dynamics simulation studies that illustrate the calculation of dynamic and thermodynamic properties, such as Stokes shifts or reorganization free energies. We then turn to the macroscopic, continuum electrostatic view. We recall the physical definition of a dielectric constant and revisit the decomposition of the free energy into a reorganization and a static term. We review some illustrative continuum studies and discuss some difficulties that can arise with the continuum approach. In conclusion, we consider recent developments that will increase the accuracy and broaden the scope of all these methods.

Cholesterol Perturbs Lipid Bilayers Nonuniversally

Jianjun Pan — 2008-05-18T18:22:24-00:00

Physical Review Letters, Vol. 100, No. 19. (2008)

Cholesterol is well known to modulate the physical properties of biomembranes. Using modern x-ray scattering methods, we have studied the effects of cholesterol on the bending modulus KC, the thickness DHH, and the orientational order parameter Sxray of lipid bilayers. We find that the effects are different for at least three classes of phospholipids characterized by different numbers of saturated hydrocarbon chains. Most strikingly, cholesterol strongly increases KC when both chains of the phospholipid are fully saturated but not at all when there are two monounsaturated chains.

Just Give Them Grants

Alan Leshner — 2008-05-16T10:24:27-00:00

Science, Vol. 320, No. 5878. (16 May 2008), 849.

10.1126/science.1159794

Atomic level computational identification of ligand migration pathways between solvent and binding site in myoglobin

JZ Ruscio — 2008-07-09T01:29:06-00:00

Proceedings of the National Academy of Sciences, Vol. 105, No. 27. (2008), pp. 9204-9209.

Myoglobin is a globular protein involved in oxygen storage and transport. No consensus yet exists on the atomic level mechanism by which oxygen and other small nonpolar ligands move between the myoglobin's buried heme, which is the ligand binding site, and surrounding solvent. This study uses room temperature molecular dynamics simulations to provide a complete atomic level picture of ligand migration in myoglobin. Multiple trajectories—providing a cumulative total of 7 μs of simulation—are analyzed. Our simulation results are consistent with and tie together previous experimental findings. Specifically, we characterize: (i) Explicit full trajectories in which the CO ligand shuttles between the internal binding site and the solvent and (ii) pattern and structural origins of transient voids available for ligand migration. The computations are performed both in sperm whale myoglobin wild-type and in sperm whale V68F myoglobin mutant, which is experimentally known to slow ligand-binding kinetics. On the basis of these independent, but mutually consistent ligand migration and transient void computations, we find that there are two discrete dynamical pathways for ligand migration in myoglobin. Trajectory hops between these pathways are limited to two bottleneck regions. Ligand enters and exits the protein matrix in common identifiable portals on the protein surface. The pathways are located in the “softer” regions of the protein matrix and go between its helices and in its loop regions. Localized structural fluctuations are the primary physical origin of the simulated CO migration pathways inside the protein.

Assessing the performance of implicit solvation models at a nucleic acid surface

F Dong — 2008-07-08T11:27:02-00:00

Physical Chemistry Chemical Physics (in press)

Implicit solvation models are popular alternatives to explicit solvent methods due to their ability to pre-average solvent behavior and thus reduce the need for computationally-expensive sampling. Previously, we have demonstrated that Poisson–Boltzmann models for polar solvation and integral-based models for nonpolar solvation can reproduce explicit solvation forces in a low-charge density protein system. In the present work, we examine the ability of these continuum models to describe solvation forces at the surface of a RNA hairpin. While these models do not completely describe all of the details of solvent behavior at this highly-charged biomolecular interface, they do provide a reasonable description of average solvation forces and therefore show significant promise for developing more robust implicit descriptions of solvent around nucleic acid systems for use in biomolecular simulation and modeling. Additionally, we observe fairly good transferability in the nonpolar model parameters optimized for protein systems, suggesting its robustness for modeling general nonpolar solvation phenomena in biomolecular systems.