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PubMed2004

Electrostatic analysis of the hepatitis C virus NS3 helicase reveals both active and allosteric site locations.

Multi-conformation continuum electrostatics (MCCE) was used to analyze various structures of the NS3 RNA helicase from the hepatitis C virus in order to determine the ionization state of amino acid side chains and their pK(a)s. In MCCE analyses of HCV helicase structures that lacked ligands, several active site residues were identified to have perturbed pK(a)s in both the nucleic acid binding site and in the distant ATP-binding site, which regulates helicase movement. In all HCV helicase structures, Glu493 was unusually basic and His369 was abnormally acidic. Both these residues are part of the HCV helicase nucleic acid binding site, and their roles were analyzed by examining the pH profiles of site-directed mutants. Data support the accuracy of MCCE predicted pK(a) values, and reveal that Glu493 is critical for low pH enzyme activation. Several key residues, which were previously shown to be involved in helicase-catalyzed ATP hydrolysis, were also identified to have perturbed pK(a)s including Lys210 in the Walker-A motif and the DExD/H-box motif residues Asp290 and His293. When DNA was present in the structure, the calculated pK(a)s shifted for both Lys210 and Asp290, demonstrating how DNA binding might lead to electrostatic changes that stimulate ATP hydrolysis.

Allosteric Site↗
PubMed2006

PDB_Hydro: incorporating dipolar solvents with variable density in the Poisson-Boltzmann treatment of macromolecule electrostatics.

We describe a new way to calculate the electrostatic properties of macromolecules which eliminates the assumption of a constant dielectric value in the solvent region, resulting in a Generalized Poisson-Boltzmann-Langevin equation (GPBLE). We have implemented a web server (http://lorentz.immstr.pasteur.fr/pdb_hydro.php) that both numerically solves this equation and uses the resulting water density profiles to place water molecules at preferred sites of hydration. Surface atoms with high or low hydration preference can be easily displayed using a simple PyMol script, allowing for the tentative prediction of the dimerization interface in homodimeric proteins, or lipid binding regions in membrane proteins. The web site includes options that permit mutations in the sequence as well as reconstruction of missing side chain and/or main chain atoms. These tools are accessible independently from the electrostatics calculation, and can be used for other modeling purposes. We expect this web server to be useful to structural biologists, as the knowledge of solvent density should prove useful to get better fits at low resolution for X-ray diffraction data and to computational biologists, for whom these profiles could improve the calculation of interaction energies in water between ligands and receptors in docking simulations.

Binding Sites↗
PubMed2001

Electrostatic recognition of matrix targeting signal by mitochondrial processing peptidase.

Mitochondrial processing peptidase (MPP), a metalloendopeptidase consisting of alpha and beta subunits, specifically recognizes a large variety of mitochondrial precursor proteins and cleaves off the N-terminal basic matrix targeting signals (MTS). Basic residues in MTS and acidic sites in MPP are required for effective processing. To elucidate whether the enzyme recognizes the MTS through electrostatic interaction, we investigated the effects of various salts on MPP activity. Decreases in the activity depended on the ionic strength and increases in the Michaelis constant value correlated clearly with the ionic strength, indicating a lower affinity of the enzyme for the substrate. Direct determination of the affinity between MPP and a MTS peptide using surface plasmon resonance showed a decrease in the association rate with high salt and that dissociation constant values were decreased. The effect of salt on the processing activity towards a variety of precursors was confirmed using five precursors with different sequences and lengths of MTS. Thus, we propose that electrostatic interactions are indispensable for the association between various MTS and MPP.

Amino Acid Sequence↗
PubMed1989

Can a simple function for the dielectric response model electrostatic effects in globular proteins?

The relationship between the effective dielectric constant that models the electrostatic effect from a charged side chain in a protein was evaluated both experimentally and theoretically. Experimental values were obtained from the shifts in pKa that resulted from point mutations of side chains in subtilisin. Theoretical values were obtained from an iterative solution to Poisson's equation that considers the dielectric response of the protein and the solvent together with charge positions. There is no simple relationship between the effective dielectric constant and the distance from the charge responsible for the interactions. For some charge positions a linear but not a direct proportional relationship of the effective dielectric with distance of separation was observed. Thus, simple models such as a linear distance-dependence for the dielectric response are not suitable to evaluate electrostatic effects in proteins.

Algorithms↗
PubMed1991

Electrostatic screening in molecular dynamics simulations.

The screened Coulombic potential has been shown to describe satisfactorily equilibrium properties like pK shifts, the effects of charged groups on redox potentials and binding constants of metal ions. To test how well the screening of the electrostatic potential describes the dynamical trajectory of a macromolecular system, a series of comparative simulations have been carried out on a protein system which explicitly included water molecules and a system in vacuo. For the system without solvent the results of using (i) the standard potential form were compared with results of (ii) the potential where the Coulomb term was modified by the inclusion of a distance dependent dielectric, epsilon (r), to model the screening effect of bulk water, and (iii) standard potential modified by reducing the charge on ionized residue side chains. All molecular dynamics simulations have been carried out on bovine pancreatic trypsin inhibitor. Comparisons between the resulting trajectories, averaged structures, hydrogen bonding patterns and properties such as solvent accessible surface area and radius of gyration are described. The results show that the dynamical behaviour of the protein calculated with a screened electrostatic term compares more favourably with the time-dependent structural changes of the full system with explicitly included water than the standard vacuum simulation.

Animals↗
PubMed1991

The role of electrostatic interactions in the mechanism of peptide bond hydrolysis by a Ser-Lys catalytic dyad.

General-base catalysis in the active site of serine proteases is carried out by the imidazole side chain of a histidine. During formation of the transition state, an adjacent carboxylic acid group stabilizes the positive charge that forms on the general-base catalyst and as a result contributes several orders of magnitude to the catalytic efficiency of these enzymes. In the recently discovered family of self-cleaving proteins exemplified by the LexA repressor of Escherichia coli, instead of the imidazole of a histidine, the active-site general-base catalyst was found to be the epsilon-amino of a lysine. The considerably higher capacity of the lysine side chain for proton acceptance raises interesting questions concerning the role of electrostatic interactions in the mechanism of proton transfer by this highly basic group. The negative charge elimination studies described here and their effects on the kmax and pK of LexA self-cleavage are consistent with a model in which electrostatic interactions between an acidic side chain and the general-base catalyst form a barrier to proton transfer. The implications are that the epsilon-amino group, unlike the imidazole group, is capable of effecting proton transfer without the intervention of a countercharge.

Bacterial Proteins↗
PubMed1994

The net energetic contribution of interhelical electrostatic attractions to coiled-coil stability.

The net energetic contribution of interhelical electrostatic attractions to coiled-coil stability has been quantitated using de novo designed synthetic coiled-coils. The synthesized model coiled-coil (EK), denoted by amino acid residues in positions e and g, which contains only interhelical ionic interactions without any possible (i, i + 3) and (i, i + 4) intrahelical ionic interaction, consists of two identical 35 residue polypeptide chains with a heptad repeat KgLaG-bAcLdEeKf. Three mutant coiled-coils were prepared where five Glu residues at e positions in EK were mutated to Gln residues (QK); five Lys residues at g positions were altered to Gln residues (EQ) or these mutations were effected at both positions e and g (QQ). The stabilities of the four coiled-coils were determined by measuring the ellipticities at 220 nm as a function of urea concentration at 20 degrees C. By using a double-mutant cycle analysis it was possible to isolate the energetic contribution of interhelical ionic attractions to coiled-coil stability from the other contributions such as helical preference and hydrophobicity. The 0.37 +/- 0.01 kcal/mol of energetic contribution of one interhelical ion pair to the coiled-coil stability was obtained from three independent comparisons. This findings suggests that a large number of weak interhelical electrostatic interactions on the surface of a protein can make a substantial contribution to protein stability. In addition, the energetic contributions of a single mutation E(-)-->Q, K(+)-->Q, Q-->E degrees and E(-)-->E degrees were also determined (delta delta G = 0.22, 0.26, and 0.46 and 0.65 kcal/mol for the single mutations, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acid Sequence↗
PubMed1995

Modelling the three-dimensional structure and the electrostatic potential field of two Cu,Zn superoxide dismutase variants from tomato leaves.

The three-dimensional structure of tomato P31 and T10 Cu,Zn superoxide dismutases (SODs) were computer modelled using the structure of the bovine enzyme as a template. The structure-essential residues retain in the models the position occupied in the other Cu,Zn SODs of known 3D structure and the overall packing of the beta-barrel is maintained. Formation of 'aromatic pairs' occurs between newly inserted aromatic residues. The number of total charges changes in the two variants and some charged residues located in the proximity of the active site in most Cu,Zn SODs disappear in tomato enzymes. Calculation of the electrostatic potential field, carried out by numerically solving the Poisson-Boltzmann equation, indicates that in both variants a negative potential field surrounds all the protein surface except the active site areas, characterized by positive potential values, as already observed in the bovine enzyme. This result confirms that coordinated mutations of charged residues have occurred in the evolution of this enzyme giving rise to a peculiar electrostatic potential distribution common to all members of this protein family.

Amino Acid Sequence↗
PubMed1995

Molecular modelling of xylose isomerase catalysis: the role of electrostatics and charge transfer to metals.

The two main steps of the mechanism of xylose-xylulose conversion catalysed by D-xylose isomerase, the ring opening of xylose and the isomerization of the opened product by hydride transfer, were investigated by molecular mechanical and molecular orbital techniques. The activation energies calculated for these reactions clearly showed that hydrogen transfer is the rate-determining step of the enzymatic isomerization and that Mg2+ ions activate whereas Zn2+ ions inhibit the reaction, in agreement with the experiments. The remarkable differences between the net charges of these ions found by molecular orbital calculations and the inspection of the protein electrostatic potential around the reaction intermediates indicate that the main role of bivalent metal ions should be the electrostatic stabilization of the substrate transition states. In order to propose a more detailed mechanism, an attempt was made to clarify the effects of nearby residues (e.g. His54, Asp57, Lys183, Asp257) in the reaction. Different isomerization mechanisms, such as through an enediol intermediate, were examined and could be excluded, in addition to the charge-relay mechanism during the ring opening.

Aldose-Ketose Isomerases↗
PubMed2005

How to improve nature: study of the electrostatic properties of the surface of alpha-lactalbumin.

It was recently shown that alpha-lactalbumin interacts with histones and simple models of histone proteins such as positively charged polyamino acids, suggesting that some fundamental aspects of the protein surface electrostatics may come into play. In the present work, the energies of charge-charge interaction in apo- and Ca(2+)-loaded alpha-lactalbumin were calculated using a Tanford-Kirkwood algorithm with either solvent accessibility correction or using a finite difference Poisson-Boltzmann method. The analysis revealed two major regions of alpha-lactalbumin that possessed highly unfavorable electrostatic potentials: (a) the Ca(2+)-binding loop and its neighboring residues and (b) the N-terminal region of the protein. Several individual mutants were prepared to neutralize specific individual surface acidic amino acids at both the N-terminus and Ca(2+)-binding loop of bovine alpha-lactalbumin. These mutants were characterized by intrinsic fluorescence, differential scanning microcalorimetry and circular dichroism. The structural and thermodynamic data agree in every case with the theoretical predictions, confirming that the N-terminal region is very sensitive to changes in charge. For example, desMet D14N mutation destabilizes protein and decreases its calcium affinity. On the other hand, desMet E1M and desMet D37N substitutions increase the thermal stability and calcium affinity. The Met E1Q is characterized by a marked increase in protein stability, whereas desMet E7Q and desMet E11L display a slight increase in calcium affinity and thermal stability. Examination of the unfavorable energy contributed by Glu1 and the energetically favorable consequences of neutralizing this residue suggests that nature may have made an error with bovine alpha-lactalbumin from the viewpoint of stabilizing structure and conformation.

Algorithms↗
PubMed2003

The effect of electrolyzed oxidative water applied using electrostatic spraying on pathogenic and indicator bacteria on the surface of eggs.

Research was conducted to compare the effectiveness of electrolyzed oxidative (EO) water applied using an electrostatic spraying system (ESS) for killing populations of bacteria that are of concern to the poultry industry. Populations of pathogenic bacteria (Salmonella typhimurium, Staphylococcus aureus, and Listeria monocytogenes), and the indicator bacterium Escherichia coli were applied to eggs and allowed to attach for 1 h. EO water completely eliminated all Salmonella typhimurium on 3, 7, 1, and 8 out of 15 eggs in Repetitions (Rep) 1, 2, 3, and 4, respectively, even when very high inoculations were used. EO water completely eliminated all Staphylococcus aureus on 12, 11, 12, and 11 out of 15 eggs in Rep 1, 2, 3, and 4, respectively. EO water completely eliminated all Listeria monocytogenes on 8, 13, 12, and 14 out of 15 eggs in Reps 1, 2, 3, and 4, respectively. EO water completely eliminated all Escherichia coli on 9, 11, 15, and 11 out of 15 eggs in Reps 1, 2, 3, and 4, respectively. Even when very high concentrations of bacteria were inoculated onto eggs (many times higher than would be encountered in industrial situations), EO water was found to be effective when used in conjunction with electrostatic spraying for eliminating pathogenic and indicator populations of bacteria from hatching eggs.

Animals↗
PubMed2005

Relative magnitudes of the effects of electrostatic image and thermophoretic forces on particles in the respiratory tract.

The National Radiological Protection Board's Advisory Group on Non-ionising Radiation has recommended research into the deposition, in the lung, of charged particles in the size range 0.005-1 microm. In vivo measurements of the temperature distribution in the respiratory tract have been used to estimate the temperature gradients in the generations up to the segmental bronchus. These gradients define the thermophoretic velocities, which oppose deposition during inhalation and assist it during exhalation. The thermophoretic forces are effective over a longer range than those due to the electrostatic image of a single charge; and, at distances greater than a few microns from the airway wall, the thermophoretic velocities of 0.02 and 0.1 microm particles are greater than those due to electrostatic drift. It is concluded that models describing the effects of electric charge on the deposition of particles with diameters of order 0.1 microm need to take account of the thermal conditions in the respiratory tract.

Aerosols↗
PubMed1984

An electrostatic precipitator for the study of airborne radioactivity.

An system has been developed to measure airborne radioactivity using electrostatic precipitation for collection and alpha-particle spectroscopy for detection. Features include good energy resolution (e.g. 170 and 300 KeV for full-width half maximum and full-width tenth maximum for 7.7-MeV alpha particles using a 7-cm2 area detector; and 52- and 122-KeV, respectively, using 1.2-cm2 area detector) and versatile computer control for collection, counting and data reduction. Aerosols bearing the radioactive atoms are deposited on a foil tape by electrostatic precipitation for a predetermined time after which the foil is moved under a solid-state detector to count the alpha-particle emissions. Activities are determined at the same frequency as samples are collected. Helium gas can be introduced at the detector to reduce energy loss and improve resolution. Although in principle certain aerosol sizes could be difficult to collect, in practice no difficulties were observed for typical environmental conditions, provided sufficiently low air-sampling rates were used. One important application is the measurement of 222Rn daughters. The sensitivity is such that detection of individual daughter concentrations less than 0.1 pCi/l. with only a 10% counting error is possible.

Air Pollution, Radioactive↗
PubMed1986

The influence of an electrostatic precipitator and a mechanical filter on Rn decay products.

In the present work the effect of an HEPA filter and an electrostatic precipitator on the behaviour of Rn decay products has been studied in laboratory conditions. Both filters were found to decrease the equilibrium factor of progeny and increase the unattached fraction of decay products. In a clean air they also decreased the activity of unattached progeny. An electrostatic precipitator was found to produce condensation nuclei which were observable when no other particle sources were present. The ozone produced by the corona discharge of the filter probably has a great effect on the production of these submicron particles. The impurities of the air were found to grow the particles and thus their influence on the behaviour of Rn decay products became in some cases significant.

Air Pollution, Radioactive↗
PubMed1986

A two-channel electrostatic model of an ionic counterport.

An alternative model is presented for an ionic counterport that depends upon electrostatic rather than steric forces. It consists of two passive ion channels, one selective for I-type ions and the other for J-type ions. The ions interact electrostatically such that the presence of one type of ion within its channel affects the motion of the second type of ion within its channel. In these circumstances it is possible to arrange that the spontaneous flow of I ions across the membrane, down their electrochemical potential gradient, pumps J ions in the opposite direction across the membrane, against their electrochemical gradient. To illustrate this type of model, a particular example of interionic coupling is described in which both types of ion interact with the electric dipole moments of some membrane-spanning alpha-helical sections of the counterport protein complex. By assuming that a group of four alpha-helices is free to rotate slightly about an axis perpendicular to the membrane, the desired form of coupling is obtained. Making simplifying assumptions, it is possible to calculate the kinetics of the model and to compare these with those expected in real counterports. Finally it is shown that, if the helix group rotation is powered by an external energy source, the pair of coupled passive ion channels can mimic a primary exchange pump such as Na+-K+ ATPase. Here both types of ion are propelled in opposite directions across the membrane and simultaneously against their electrochemical potential gradients.

Animals↗
PubMed2002

Electrostatics and proton transfer in photosynthetic water oxidation.

Photosystem II (PSII) oxidizes two water molecules to yield dioxygen plus four protons. Dioxygen is released during the last out of four sequential oxidation steps of the catalytic centre (S(0) --> S(1), S(1) --> S(2), S(2) --> S(3), S(3) --> S(4) --> S(0)). The release of the chemically produced protons is blurred by transient, highly variable and electrostatically triggered proton transfer at the periphery (Bohr effect). The extent of the latter transiently amounts to more than one H(+)/e(-) under certain conditions and this is understood in terms of electrostatics. By kinetic analyses of electron-proton transfer and electrochromism, we discriminated between Bohr-effect and chemically produced protons and arrived at a distribution of the latter over the oxidation steps of 1 : 0 : 1 : 2. During the oxidation of tyr-161 on subunit D1 (Y(Z)), its phenolic proton is not normally released into the bulk. Instead, it is shared with and confined in a hydrogen-bonded cluster. This notion is difficult to reconcile with proposed mechanisms where Y(Z) acts as a hydrogen acceptor for bound water. Only in manganese (Mn) depleted PSII is the proton released into the bulk and this changes the rate of electron transfer between Y(Z) and the primary donor of PSII P(+)(680) from electron to proton controlled. D1-His190, the proposed centre of the hydrogen-bonded cluster around Y(Z), is probably further remote from Y(Z) than previously thought, because substitution of D1-Glu189, its direct neighbour, by Gln, Arg or Lys is without effect on the electron transfer from Y(Z) to P(+)(680) (in nanoseconds) and from the Mn cluster to Y(ox)(Z).

Binding Sites↗
PubMed2025

An electrostatic repulsion model of centromere organisation.

During cell division, chromosomes reorganise into compact bodies in which centromeres localise precisely at the chromatin surface1-4 to enable kinetochore-microtubule interactions essential for genome segregation5-8. The physical principles guiding this centromere positioning remain unknown. Here, we reveal that human core centromeres are directed to the chromatin surface by repulsion of centromere-associated proteins - independent of condensin-mediated loop extrusion and microtubule engagement. Using cellular perturbations, biochemical reconstitution, and multiscale molecular dynamics simulations, we show that chromatin surface localisation emerges from repulsion between condensed chromatin and both the kinetochore and the highly negatively charged centromere protein, CENP-B. Together, these elements form a centromeric region composed of two domains with opposing affinities, one favouring integration within the mitotic chromosome and the other favouring exposure to the surrounding cytoplasm, thereby driving surface positioning. Tethering synthetic negatively charged proteins to chromatin was sufficient to recapitulate this surface localisation in cells and in vitro, indicating that electrostatic repulsion is a key determinant of surface localisation. These findings demonstrate that centromere layering is not hardwired by chromatin folding patterns but instead emerges from phase separation in chromatin. Our work uncovers electrostatic polarity as a general and programmable mechanism to spatially organise chromatin.

Journal Article↗
PubMed1999

Electrostatics of a modulated membrane with specific adsorption.

We present a simple model for the electrostatic properties of a modulated membrane separating two different electrolyte solutions. The model is based on an extension to linear Gouy-Chapman theory. Starting from a Hamiltonian which contains a singular part for the surface contributions, we obtain within the mean-field approach a set of equations which allows us to study the equilibrium between the diffuse and singular parts of the charge carriers. It is shown that the interface modulation leads to a higher potential of zero charge compared to the flat system. The value of this effect depends on the interplay between the height and the characteristic length of the interface modulation and the Debye lengths on both sides, even if the adsorption occurs only on one side of the interface. In the latter case, the side where no adsorption occurs locally exhibits a diffuse charge distribution, which averages to zero, but which makes a contribution to the overall potential drop across the interface. We also calculate the electrostatic contribution to the elastic bending modulus of the membrane and show that specific adsorption of ions can destabilize the flat interface.

Journal Article↗