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PubMed2005

Monte Carlo simulations of the solution structure of simple alcohols in water-acetonitrile mixtures.

Monte Carlo simulations have been performed to explore the solution structure of ethyl, isopropyl, isobutyl, and tertiary butyl alcohols in pure water, pure acetonitrile, and different mixtures of the two solvents. The explicit solvent studies in NpT ensembles at T = 298 K illustrate that the solute "discriminates" the solvent's components and that the composition of the first solvation shell differs from that of the bulk solution. Since the polarizable continuum dielectric method (PCM) does not presently model the solvation of molecules with both polar and apolar sites in mixed protic solvents, we suggest a direction for further program development wherein a continuum dielectric method would accept more than one solvent and the solute sites would be solvated by user-defined solvent components. The prevailing solvation model will be determined upon the lowest free energy calculated for a particular solvation pattern of the solute having a specific conformational/tautomeric state. Characterization of equilibrium hydrogen-bond formation becomes a complicated problem that depends on the chemical properties of the solute and its conformation, as well as upon the varying nature of the first solvation shell. For example, while the number of hydrogen bonds to secondary and tertiary alcohol solutes are nearly constant in pure water and in water-acetonitrile mixtures with at least 50% water content, the number of hydrogen bonds to primary alcohols gradually decreases for most of their conformations when acetonitrile content is increased. Nonetheless, the calculations indicate that O-H...O(water) hydrogen bonds are still possible in a small fraction of the arrangements for the solution models with water content of 30% or less. The isopentene solute does not form any observable hydrogen bonds, despite having an electron-rich, double-bond site.

Acetonitriles↗
PubMed2004

Langevin dynamics in constant pressure extended systems.

The advantages of performing Langevin dynamics in extended systems are discussed. A simple Langevin dynamics scheme for producing the canonical ensemble is reviewed, and is then extended to the Hoover ensemble. We show that the resulting equations of motion generate the isobaric-isothermal ensemble. The Parrinello-Rahman ensemble is then discussed and we show that despite the presence of intrinsic probability gradients in this system, a Langevin dynamics approach samples the extended phase space in the correct fashion. The implementation of these methods in the ab initio plane wave density functional theory code CASTEP [M. D. Segall, P. L. D. Lindan, M. J. Probert, C. J. Pickard, P. J. Hasnip, S. J. Clarke, and M. C. Payne, J. Phys.: Condens. Matter 14, 2717 (2003)] is demonstrated.

Journal Article↗
PubMed1984

Dihydropyridine derivatives prolong the open state of Ca channels in cultured cardiac cells.

The dihydropyridine derivatives CGP 28392 and BAY K 8644 exert a strong positive inotropic effect in mammalian cardiac muscle, presumably by increasing Ca influx during the action potential. Analysis of the drug effects at the level of single Ca channels by means of the patch-clamp method revealed complicated changes in the kinetics of channel gating. The prevailing effect is a prolongation of the mean open time of Ca channels. In addition, the intervals between channel openings can be slightly prolonged. Ensemble averages of single-channel traces showed a concentration-dependent increase in the mean current amplitude by the drugs. In contrast to beta-adrenoceptor agonists, the increase in Ca current by the dihydropyridine derivatives is not associated with an increase in the intracellular cyclic AMP level.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed1999

The oxidative refolding of hen lysozyme and its catalysis by protein disulfide isomerase.

The oxidative refolding of hen lysozyme has been studied by a variety of time-resolved biophysical methods in conjunction with analysis of folding intermediates using reverse-phase HPLC. In order to achieve this, refolding conditions were designed to reduce aggregation during the early stages of the folding reaction. A complex ensemble of relatively unstructured intermediates with on average two disulfide bonds is formed rapidly from the fully reduced protein after initiation of folding. Following structural collapse, the majority of molecules slowly form the four-disulfide-containing fully native protein via rearrangement of a highly native-like, kinetically trapped intermediate, des-[76-94], although a significant population (approximately 30%) appears to fold more quickly via other three-disulfide intermediates. The folding catalyst PDI increases dramatically both yields and rates of lysozyme refolding, largely by facilitating the conversion of des-[76-94] to the native state. This suggests that acceleration of the folding rate may be an important factor in avoiding aggregation in the intracellular environment.

Animals↗
PubMed1991

cGMP inhibits the activity of single calcium channels in embryonic chick heart cells.

Effects of cGMP on the slow (L-type) Ca2+ channels of cultured chick embryonic cardiomyocytes were investigated by a cell-attached patch-clamp method. Superfusion of the single cells with 8-bromo-cGMP, a membrane-permeable derivative of cGMP, inhibited the single-channel activity. The cyclic nucleotide decreased, in a concentration-dependent manner, the ensemble averaged currents obtained from multichannel patches. 8-Bromo-cGMP (1 mM) completely abolished the currents (n = 8), whereas 0.1 mM only slightly decreased the currents (n = 4). The influence of cGMP on the characteristics of the single Ca2+ channels was examined using 0.3 mM 8-bromo-cGMP. Unit amplitude and slope conductance of the Ca2+ channel was not changed (25 pS in control versus 24 pS in the presence of cGMP). Analysis of single-channel kinetics showed that cGMP prolonged the slow time constant for the closed-time histogram (from 6.7 to 15.4 msec); the other time constants (for the open-time and closed-time histograms) were not affected. cGMP-induced inhibition of the Ca2+ channels may be mediated by cGMP-dependent protein kinase, because 8-bromo-cGMP is a potent activator of this protein kinase and does not stimulate cAMP hydrolysis. The present results suggest that cGMP opposes the effects of cAMP on the L-type Ca2+ channels in myocardial cells.

Animals↗
PubMed1990

Clinical evaluation of an ensemble-averaging impedance cardiograph for monitoring stroke volume during spontaneous breathing.

Simultaneous determination of stroke volume (SV) with an ensemble-averaging impedance cardiograph (AIGG) and the thermodilution technique (TD) was compared in 10 patients scheduled for major vascular surgery. A small, successive increase in SV was achieved by a step-wise infusion of dextran-70 and elevation of the patient's legs. The patients were allowed to breathe normally during the measurement procedures. There was no difference between the ability of AICG and TD to monitor changes in SV and the correlation coefficient for the measurement of changes in SV by the two methods was 0.88. There was no difference between the reproducibility of AICG- (4.6 ml) and TD- (9.2 ml) determined SV or between the coefficient of variation for AICG (4.8%) and TD (9.9%). The mean difference between AICG- and TD-determined SV at the different measurement points (range 1.3-4.2 ml) was well within acceptable limits. In conclusion, the ensemble-averaging impedance cardiograph described in this study was found to be reliable for monitoring changes in SV during uninterrupted, spontaneous breathing.

Aged↗
PubMed2004

MMTSB Tool Set: enhanced sampling and multiscale modeling methods for applications in structural biology.

We describe the Multiscale Modeling Tools for Structural Biology (MMTSB) Tool Set (https://mmtsb.scripps.edu/software/mmtsbToolSet.html), which is a novel set of utilities and programming libraries that provide new enhanced sampling and multiscale modeling techniques for the simulation of proteins and nucleic acids. The tool set interfaces with the existing molecular modeling packages CHARMM and Amber for classical all-atom simulations, and with MONSSTER for lattice-based low-resolution conformational sampling. In addition, it adds new functionality for the integration and translation between both levels of detail. The replica exchange method is implemented to allow enhanced sampling of both the all-atom and low-resolution models. The tool set aims at applications in structural biology that involve protein or nucleic acid structure prediction, refinement, and/or extended conformational sampling. With structure prediction applications in mind, the tool set also implements a facility that allows the control and application of modeling tasks on a large set of conformations in what we have termed ensemble computing. Ensemble computing encompasses loosely coupled, parallel computation on high-end parallel computers, clustered computational grids and desktop grid environments. This paper describes the design and implementation of the MMTSB Tool Set and illustrates its utility with three typical examples--scoring of a set of predicted protein conformations in order to identify the most native-like structures, ab initio folding of peptides in implicit solvent with the replica exchange method, and the prediction of a missing fragment in a larger protein structure.

Computer Simulation↗
PubMed1993

Distribution of type I Fc epsilon-receptors on the surface of mast cells probed by fluorescence resonance energy transfer.

The aggregation state of type I Fc epsilon-receptors (Fc epsilon RI) on the surface of single living mast cells was investigated by resonance fluorescence energy transfer. Derivatization of Fc epsilon RI specific ligands, i.e., immunoglobulin E or Fab fragments of a Fc epsilon RI specific monoclonal antibody, with donor and acceptor fluorophores provided a means for measuring receptor clustering through energy transfer between the receptor probes. The efficiency of energy transfer between the ligands carrying distinct fluorophores was determined on single cells in a microscope by analyzing the photobleaching kinetics of the donor fluorophore in the presence and absence of receptor ligands labeled with acceptor fluorophores. To rationalize the energy transfer data, we developed a theoretical model describing the dependence of the energy transfer efficiency on the geometry of the fluorescently labeled macromolecular ligands and their aggregation state on the cell surface. To this end, the transfer process was numerically calculated first for one pair and then for an ensemble of Fc epsilon RI bound ligands on the cell surface. The model stipulates that the aggregation state of the Fc epsilon RI is governed by an attractive lipid-protein mediated interaction potential. The corresponding pair-distribution function characterizes the spatial distribution of the ensemble. Using this approach, the energy transfer efficiency of the ensemble was calculated for different degrees of receptor aggregation. Comparison of the theoretical modeling results with the experimental energy transfer data clearly suggests that the Fc epsilon RI are monovalent, randomly distributed plasma membrane proteins. The method provides a novel approach for determining the aggregation state of cell surface components.

Animals↗
PubMed2006

X-ray diffraction "fingerprinting" of DNA structure in solution for quantitative evaluation of molecular dynamics simulation.

Solution state x-ray diffraction fingerprinting is demonstrated as a method for experimentally assessing the accuracy of molecular dynamics (MD) simulations. Fourier transforms of coordinate data from MD simulations are used to produce reciprocal space "fingerprints" of atomic pair distance correlations that are characteristic of the ensemble and are the direct numerical analogues of experimental solution x-ray diffraction (SXD). SXD experiments and MD simulations were carried out to test the ability of experiment and simulation to resolve sequence-dependent modifications in helix conformation for B-form DNA. SXD experiments demonstrated that solution-state poly(AT) and poly(A)-poly(T) duplex DNA sequences exist in ensembles close to canonical B-form and B'-form structures, respectively. In contrast, MD simulations analyzed in terms of SXD fingerprints are shown to deviate from experiment, most significantly for poly(A)-poly(T) duplex DNA. Compared with experiment, MD simulation shortcomings were found to include both mismatches in simulated conformer structures and number population within the ensembles. This work demonstrates an experimental approach for quantitatively evaluating MD simulations and other coordinate models to simulate biopolymer structure in solution and suggests opportunities to use solution diffraction data as experimental benchmarks for developing supramolecular force fields optimized for a range of in situ applications.

DNA↗
PubMed2006

Probing genuine strong interactions and post-translational modifications in the heterogeneous yeast exosome protein complex.

The characterization of heterogeneous multicomponent protein complexes, which goes beyond identification of protein subunits, is a challenging task. Here we describe and apply a comprehensive method that combines a mild affinity purification procedure with a multiplexed mass spectrometry approach for the in-depth characterization of the exosome complex from Saccharomyces cerevisiae expressed at physiologically relevant levels. The exosome is an ensemble of primarily 3' --> 5' exoribonucleases and plays a major role in RNA metabolism. The complex has been reported to consist of 11 proteins in molecular mass ranging from 20 to 120 kDa. By using native macromolecular mass spectrometry we measured accurate masses (around 400 kDa) of several (sub)exosome complexes. Combination of these data with proteolytic peptide LC tandem mass spectrometry using a linear ion trap coupled to a FT-ICR mass spectrometer and intact protein LC mass spectrometry provided us with the identity of the different exosome components and (sub)complexes, including the subunit stoichiometry. We hypothesize that the observed complexes provide information about strongly and weakly interacting exosome-associated proteins. In our analysis we also identified for the first time phosphorylation sites in seven different exosome subunits. The phosphorylation site in the Rrp4 subunit is fully conserved in the human homologue of Rrp4, which is the only previously reported phosphorylation site in any of the human exosome proteins. The described multiplexed mass spectrometry-based procedure is generic and thus applicable to many different types of cellular molecular machineries even if they are expressed at endogenous levels.

Amino Acid Sequence↗
PubMed2002

Pathway diversity and concertedness in protein folding: an ab-initio approach.

Making use of an ab-initio folding simulator, we generate in vitro pathways leading to the native fold in moderate size single- domain proteins. The assessment of pathway diversity is not biased by any a priori information on the native fold. We focus on two study cases, hyperthermophile variant of protein G domain (1gb4) and ubiquitin (1ubi), with the same topology but different context dependence in their native folds. We demonstrate that a quenching of structural fluctuations is achieved once the proteins find a stationary plateau maximizing the number of highly protected hydrogen bonds. This enables us to identify the folding nucleus and show that folding does not become expeditious until a concerted event takes place generating a topology able to prevent water attack on a maximal number of hydrogen bonds. This result is consistent with the standard nucleation mechanism postulated for two-state folders. Pathway diversity is correlated with the extent of conflict between local structural propensity and large-scale context, rather than with contact order: In highly context-dependent proteins, the success of folding cannot rely on a single fortuitous event in which local propensity is overruled by large-scale effects. We predict mutational Pi values on individual pathways, compute ensemble averages and predict extent of surface burial and percentage of hydrogen bonding on each component of the transition state ensemble, thus deconvoluting individual folding-route contributions to the averaged two-state kinetic picture. Our predicted kinetic isotopic effects find experimental support and lead to further probes. Finally, the molecular redesign potentiality of the method, aimed at increasing folding expediency, is explored.

Algorithms↗
PubMed2005

Conservation and specialization in PAS domain dynamics.

The PAS (Per-ARNT-Sim) superfamily is presented as a well-suited study case to demonstrate how comparison of functional motions among distant homologous proteins with conserved fold characteristics may give insight into their functional specialization. Based on the importance of structural flexibility of the receptive structures in anticipating the signal-induced conformational changes of these sensory systems, the dynamics of these structures were analysed. Molecular dynamics was proved to be an effective method to obtain a reliable picture of the dynamics of the crystal structures of HERG, phy3, PYP and FixL, provided that an extensive conformational space sampling is performed. Other reliable sources of dynamic information were the ensembles of NMR structures of hPASK, HIF-2alpha and PYP. Essential dynamics analysis was successfully employed to extract the relevant information from the sampled conformational spaces. Comparison of motion patterns in the essential subspaces, based on the structural alignment, allowed identification of the specialized region in each domain. This appears to be evolved in the superfamily by following a specific trend, that also suggests the presence of a limited number of general solutions adopted by the PAS domains to sense external signals. These findings may give insight into unknown mechanisms of PAS domains and guide further experimental studies.

Adiantum↗
PubMed2003

Replica limit of the toda lattice equation.

In a recent breakthrough Kanzieper showed that it is possible to obtain exact nonperturbative random matrix results from the replica limit of the corresponding Painlevé equation. In this article we analyze the replica limit of the Toda lattice equation and obtain exact expressions for the two-point function of the Gaussian unitary ensemble and the resolvent of the chiral unitary ensemble. In the latter case both the fully quenched and the partially quenched limit are considered. This derivation explains in a natural way the appearance of both compact and noncompact integrals, the hallmark of the supersymmetric method, in the replica limit of the expression for the resolvent.

Journal Article↗
PubMed1992

Weighted averaging of evoked potentials.

Weighted averages of brain evoked potentials (EP's) are obtained by weighting each single EP sweep prior to averaging. These weights are shown to maximize the signal-to-noise ratio (SNR) of the resulting average if they satisfy a generalized eigenvalue problem involving the correlation matrices of the underlying signal and noise components. The signal and noise correlation matrices are difficult to estimate and the solution of the generalized eigenvalue problem is often computationally impractical for real-time processing. Correspondingly, a number of simplifying assumptions about the signal and noise correlation matrices are made which allow an efficient method of approximating the maximum SNR weights. Experimental results are given using actual auditory EP data which demonstrate that the resulting weighted average has estimated SNR's that are up to 21% greater than the conventional ensemble average SNR.

Artifacts↗
PubMed2001

Accessing molecular dynamics in cells by fluorescence correlation spectroscopy.

Fluorescence correlation spectroscopy (FCS) analyzes spontaneous fluctuations in the fluorescence emission of small molecular ensembles, thus providing information about a multitude of parameters, such as concentrations, molecular mobility and dynamics of fluorescently labeled molecules. Performed within diffraction-limited confocal volume elements, FCS provides an attractive alternative to photobleaching recovery methods for determining intracellular mobility parameters of very low quantities of fluorophores. Due to its high sensitivity sufficient for single molecule detection, the method is subject to certain artifact hazards that must be carefully controlled, such as photobleaching and intramolecular dynamics, which introduce fluorescence flickering. Furthermore, if molecular mobility is to be probed, nonspecific interactions of the labeling dye with cellular structures can introduce systematic errors. In cytosolic measurements, lipophilic dyes, such as certain rhodamines that bind to intracellular membranes, should be avoided. To study free diffusion, genetically encoded fluorescent labels such as green fluorescent protein (GFP) or DsRed are preferable since they are less likely to nonspecifically interact with cellular substructures.

Carbocyanines↗
PubMedDate not supplied

[Structure and conformational properties of the HIV Thailand gp120 immunodominant epitope].

NMR data and the previously developed theoretical method were used to determine the three-dimensional structure of the immunodominant epitope (IDE) of the HIVThailand. protein gp120. The best energy IDE conformers consistent with the theoretical and experimental data were calculated, and their ensemble was shown to give rise to the main chain folds found earlier in examining the HIVMN IDE structure. The gp120 IDE is supposed to behave as a metastable oligopeptide that, depending on the microenvironment, largely assumes one of the conformations from the ensemble. The results are discussed in the light of literature data on HIV-1 IDE structure.

Epitopes↗
PubMed2005

Structure of inhomogeneous attractive and repulsive hard-core yukawa fluid: grand canonical Monte Carlo simulation and density functional theory study.

A density functional theory is proposed for an inhomogeneous hard-core Yukawa (HCY) fluid based on Rosenfeld's perturbative method. The excess Helmholtz energy functional is derived from a modified fundamental measure theory for the hard-core repulsion and a quadratic functional Taylor expansion for the long-ranged attractive or repulsive interactions. To test the established theory, grand canonical ensemble Monte Carlo simulations are carried out to simulate the density profiles of attractive and repulsive HCY fluid near a wall. Comparison with the results from the Monte Carlo simulations shows that the present density functional theory gives accurate density profiles for both attractive and repulsive HCY fluid near a wall. Both the present theory and simulations suggest that there is depletion for attractive HCY fluid at low temperature, but no depletion is found for repulsive HCY fluid. The calculated results indicate that the present density functional theory is better than those of the modified version of the Lovett-Mou-Buff-Wertheim and other density functional theories. The present theory is simple in form and computationally efficient. It predicts accurate radial distribution functions of both attractive and repulsive HCY fluid except for the repulsive case at high density, where the theory overestimates the radial distribution function in the vicinity of contact.

Chemistry, Physical↗
PubMed1993

Biasing a Monte Carlo chain growth method with Ramachandran's plot: application to twenty-L-alanine.

In this paper, we explore the possibility of using experimental observations in the Monte Carlo chain growth method that we have previously developed. In this method, the macromolecule (peptide, protein, nuclei acid, etc.) is grown atom-by-atom (or residue-by-residue, etc.) and partial chains are replicated according to their Boltzmann weights. Once the molecule completed, we are left with a Boltzmann-distributed ensemble of configurations. For long molecules, an efficient sampling of the (extremely large) phase space is difficult for obvious reasons (existence of many local minima, limited computer memory, etc.). In the case in which one is mainly interested in the low energy conformations, we have incorporated in the growth scheme experimental observations taken from the Protein Data Banks. More precisely, we have considered the case of twenty-L-alanine and we have used the (experimental) Ramachandran's plot for this residue. The biased growth procedure goes as follows: (a) each time one adds along the main backbone chain, either a carbon atom belonging to a carbonyl group, or a nitrogen atom, its dihedral angle (theta) or (psi) is drawn with a probability law that reflects the experimental Ramachandran (theta, psi) plot; (b) the bias introduced in this way is canceled through an extra term in the energy (replication energy = true energy + bias energy); (c) the configurations, generated at T = 1000 K, are then energy minimized.(ABSTRACT TRUNCATED AT 250 WORDS)

Alanine↗