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PubMedDate not supplied

Molecular electrostatic potential-anthelmintic activity relationships of 5H-mebendazole and some related heterocyclic carbamates.

5H-Mebendazole and some related heterocyclic methyl carbamates were synthesized and their anthelmintic activity against Caenorhabditis elegans was determined. In order to study the influence of the heteroaromatic region with regard to the carbamate moiety on biological activity, the molecular electrostatic potentials (MEP) of all structures were calculated and a structure-activity relationship (SAR) was established. The electrostatic pattern of activity includes two minima of the carbamate moiety, a third heterocyclic minimum, and a pi-electronic region.

Animals↗
PubMed1985

Electrostatic deformation of DNA by a DNA-binding protein.

Complementary electrostatic interactions between negatively charged B-DNA and a positively charged array on the lambda Cro repressor protein are shown to substantially contribute to the formation energy of sequence-specific and nonspecific Cro-DNA complexes. The electrostatic interactions favor Cro binding to a bent form of DNA, a geometry which optimizes hydrogen-bonding contacts between Cro and exposed base pair groups in the DNA major groove.

DNA↗
PubMed1993

A novel electrostatic approach to enzyme mechanisms: carbonic anhydrase as an example.

A novel electrostatic approach to the manner in which enzymes catalyze reactions is developed. In this development, the author's interpretations of, and additions to, the late K. Fajans' theory of electronic structure (referred to as the Quanticule theory of chemical binding) are presented. This theory is based upon electron densities, in analogy to density functional theory. It is used to derive formulations of molecular structure, (Fajans' formulations) which show the charges of the atomic components. These charges are shown to be reduced by polarization to what are commonly referred to as partial charges. These formulations relate to the exchange of charged atomic components during reactions. The relevance of the formulations to the catalytic activity of enzymes is illustrated with carbonic anhydrase. When viewed in terms of Fajans' formulations, the active site is seen to consist of an array of charged atoms. The positive and negative charges tend to alternate. When closely positioned, these charges provide a basis for drawing atomic components of the molecules, which are exchanged in a given reaction, into the new positions. The charges are shown to be related to the binding of substrates to the enzyme and the positioning of them so that they can interact, to the reaction itself, to an essential proton transfer, and to the dissociation of the product from the enzyme. This more extensive scope of electrostatic interactions provides a more simple view of the manner in which the catalysis is accomplished. Such catalysis is consistent with a number of other proposals about enzyme mechanisms, and appears to be applicable to a large majority of enzyme-catalyzed reactions.

Binding Sites↗
PubMed1998

Influence of the electrostatic charge of lipoprotein particles on the activity of the human plasma phospholipid transfer protein.

The aim of the present study was to determine the effect of the electrostatic charge of lipoproteins on the phospholipid transfer activity of the plasma phospholipid transfer protein (PLTP). Progressive decreases in the PLTP-mediated phospholipid transfer rates were observed when the surface potential of isolated high density lipoproteins (HDL) was either reduced from -11.7 mV down to -15.7 mV by succinylation of apolipoprotein lysyl residues, or increased from -11.6 mV up to -10.9 mV by replacing apolipoprotein (apo) A-I by apoA-II. When succinylated low density lipoprotein (LDL) series with surface potentials ranging between -4.3 mV and -14.3 mV were used, successive increase and decrease in phospholipid transfer rates were observed along the electronegativity scale. When various plasma HDL subfractions with surface potentials ranging from -10.5 mV to -12.5 mV were separated by anion exchange chromatography, PLTP-mediated phospholipid transfer activity increased progressively with HDL electronegativity until maximal lipid transfer rates were reached for a mean HDL surface potential of -11.6 mV. As the electronegativity of plasma HDL subfractions kept increasing beyond the optimal value, a progressive decrease in PLTP activity was observed. Striking parallelism between cholesteryl ester transfer protein (CETP) and PLTP transfer activity curves obtained with each HDL series were noted, and the optimal HDL surface potential values were remarkably similar, approximating -11.6 mV in all the experiments. With isolated plasma LDL subfractions with surface potentials ranging from -3.5 mV to -5.0 mV, a linear rise in PLTP activity was observed. In conclusion, data of the present study indicate that, like CETP, the activity of PLTP is influenced by electrostatic interactions with lipoproteins.

Apolipoprotein A-I↗
PubMed1996

Experimental and theoretical study of electrostatic effects on the isoelectric pH and the pKa of the catalytic residue His-102 of the recombinant ribonuclease from Bacillus amyloliquefaciens (barnase).

Barnase, the guanine specific ribonuclease of Bacillus amyloliquefaciens, was subjected to mutations in order to alter the electrostatic properties of the enzyme. Ser-85 was mutated into Glu with the goal to introduce an extra charge in the neighborhood of His-102. A double mutation (Ser-85-Glu and Asp-86-Asn) was introduced with the same purpose but without altering the global charge of the enzyme. A similar set of mutations was made using Asp at position 85. For all mutants the pI was determined using the technique of isoelectric focusing and calculated on the basis of the Tanford-Kirkwood theory. When Glu was used to replace Ser-85, the correlation between the experimental and the calculated values was perfect. However, in the Ser-85-Asp mutant, the experimental pI drop is bigger than the calculated one, and in the double mutant (Ser-85-Asp and Asp-86-Asn) the compensation is not achieved. The effect of the mutations on the pKa of His-102 can be determined from the pH dependence of the kcat/KM for the hydrolysis of dinucleotides, e.g., GpC. The effect can also be calculated using the the method of Honig. In this case the agreement is very good for the Glu-mutants and the single Asp-mutant, but less for the double Asp-mutant. The global stability of the Asp-mutants is, however, the same as the wild type, as shown by stability studies using urea denaturation. Molecular dynamics calculations, however, show that in the double Asp-mutant His-102 (H+) swings out of its pocket to make a hydrogen bridge with Gin-104 which should cause an additional pKa rise. The effect of the Glu-mutations was also tested on all the kinetic parameters for GpC and the cyclic intermediate G > p at pH 6.5, for RNA at pH 8.0, and for poly(A) at pH 6.2. The effect of the mutations is rather limited for the dinucleotide and the cyclic intermediate, but a strong increase of the KM is observed in the case of the single mutant (extra negative charge) with polymeric substrates. These results indicate that the extra negative charge has a strong destabilizing effect on the binding of the polymeric substrates in the ground state and the transition state complex. A comparison with the structure of bound tetranucleotides (Buckle, A.M. and Fersht, A.R., Biochemistry 33:1644-1653, 1994) shows that the extra negative charge points towards the P2 site.

Bacillus↗
PubMed1998

Prediction of the three-dimensional structure of proteins using the electrostatic screening model and hierarchic condensation.

We describe a method for predicting the three-dimensional (3-D) structure of proteins from their sequence alone. The method is based on the electrostatic screening model for the stability of the protein main-chain conformation. The free energy of a protein as a function of its conformation is obtained from the potentials of mean force analysis of high-resolution x-ray protein structures. The free energy function is simple and contains only 44 fitted coefficients. The minimization of the free energy is performed by the torsion space Monte Carlo procedure using the concept of hierarchic condensation. The Monte Carlo minimization procedure is applied to predict the secondary, super-secondary, and native 3-D structures of 12 proteins with 28-110 amino acids. The 3-D structures of the majority of local secondary and super-secondary structures are predicted accurately. This result suggests that control in forming the native-like local structure is distributed along the entire protein sequence. The native 3-D structure is predicted correctly for 3 of 12 proteins composed mainly from the alpha-helices. The method fails to predict the native 3-D structure of proteins with a predominantly beta secondary structure. We suggest that the hierarchic condensation is not an appropriate procedure for simulating the folding of proteins made up primarily from beta-strands. The method has been proved accurate in predicting the local secondary and super-secondary structures in the blind ab initio 3-D prediction experiment.

Algorithms↗
PubMed1998

Electrostatics, allostery, and activity of the yeast chorismate mutase.

The predicted active site of chorismate mutase of baker's yeast Saccharomyces cerevisiae has been studied by continuum electrostatics, molecular surface/volume calculations, and molecular modeling. Our study shows that despite being subject to an allosteric transition, the enzyme's active-site pocket neither decreased in volume nor deformed significantly in shape between the active R state and the inactive T state. We find that the polar atmosphere in the pocket is responsible for the enzyme's affinity. A single amino acid, Glu23, can adequately account for the atmospheric variation. This residue swings into the active-site pocket from the R state to the T state. In the R state, Glu23 on helix H2 doubly pairs with Arg204 and Lys208 of H11, which is packed against H2. In the T state, a slide occurs between H11 and H2 such that Glu23 can no longer interact with Lys208 and competes with Asp24 for interacting with Arg204. Consequently, Glu23 is found in the T state to couple with Arg157, an active-site residue critical to substrate binding. The tandem sliding of H11 in both monomers profoundly changes the interactions in the dimer interface. The loop between H11 and H12 demonstrates the largest conformational change. Hence, we establish a connection between the allosteric transition and the activity of the enzyme. The conformational change in the transition is suggested to propagate into the active-site pocket via a series of polar interactions that result in polarity reversal in the active-site pocket, which regulates the enzyme's activity.

Allosteric Regulation↗
PubMed1996

An external source 7 T Fourier transform ion cyclotron resonance mass spectrometer with electrostatic ion guide.

An external source 7 T Fourier transform ion cyclotron resonance (FTICR) mass spectrometer offers three main novel features. First, a 9-way ion-source cross allows for mounting of up to three ionization sources simultaneously, thereby minimizing 'downtime' for changing ion sources. Second, an electrostatic (wire-in-cylinder) ion guide transports the ions approximately 1.5 m from the ion source to the ion trap for mass analysis, through a large magnetic field gradient. Third, the system operates from a modular data system described elsewhere in this issue. Luteinizing hormone-releasing hormone (LH-RH) matrix-assisted laser desorption/ionization (MALDI) FTICR positive-ion mass spectra exhibit signal-to-noise ratio greater than 1000:1 and mass resolving power, m/delta m 50% > 100,000. Laser-induced fragmentation of bradykinin demonstrates the ability of the ion guide to transmit both molecular and fragment ions simultaneously. Ultra-high resolution (average resolving power approximately 400,000) was achieved for poly(ethylene glycol) of specified number-average molecular weight, Mn approximately 3400. Future installation of an electrospray source to the ion-source cross should allow for better characterization of the performance of the ion guide.

Bradykinin↗
PubMed1996

Exploration of the conformational space of oxytocin and arginine-vasopressin using the electrostatically driven Monte Carlo and molecular dynamics methods.

Conformational analysis of the neurohypophyseal hormones oxytocin (OT) and arginine-vasopressin (AVP) has been carried out using two different computational approaches and three force fields, namely by the Electrostatically Driven Monte Carlo (EDMC) method, with the Empirical Conformational Energy Program for Peptides (ECEPP/3) force field or with the ECEPP/3 force field plus a hydration-shell model, and by simulated-annealing molecular dynamics with the Consistent Valence Force Field (CVFF). The low-energy conformations obtained for both hormones were classified using the minimal-tree clustering algorithm and characterized according to the locations of beta-turns in the cyclic moieties. Calculations with the CVFF force field located conformations with a beta-turn at residues 3 and 4 as the lowest energy ones both for OT and for AVP. In the ECEPP/3 force field the lowest energy conformation of OT contained a beta-turn at residues 2 and 3, conformations with this location of the turn being higher in energy for AVP. The latter difference can be attributed to the difference in the size of the side chain in position 3 of the sequences: the bulkier phenylalanine residue of AVP in combination with the bulky Tyr2 residue hinders the formation of a turn at residues 2 and 3. Conformations of OT and AVP with a turn at residues 3,4 were in the best agreement with the x-ray structures of deaminooxytocin and pressinoic acid (the cyclic moiety of vasopressin), respectively, and with the nmr-derived distance constraints. Generally, the low-energy conformations obtained with the hydration-shell model were in a better agreement with the experimental data than the conformations calculated in vacuo. It was found, however, that the obtained low-energy conformations do not satisfy all of the nmr-derived distance constraints and the nuclear Overhauser effect pattern observed in nmr studies can be fully explained only by assuming a dynamic equilibrium between conformations with beta-turns at residues 2,3, 3,4, and 4,5. The low-energy structures of OT with a beta-turn at residues 2,3 have the disulfide ring conformations close to the model proposed recently for a potent bicyclic antagonist of OT [M. D. Shenderovich et al. (1994) Polish Journal of Chemistry, Vol. 25, pp. 921-927], although the native hormone differs from the bicyclic analogue by the conformation of the C-terminal tripeptide. This finding confirms the hypothesis of different receptor-bound conformations of agonists and antagonists of OT.

Amino Acid Sequence↗
PubMed1998

New developments of the electrostatically driven Monte Carlo method: test on the membrane-bound portion of melittin.

The electrostatically driven Monte Carlo (EDMC) method has been greatly improved by adding a series of new features, including a procedure for cluster analysis of the accepted conformations. This information is used to guide the search for the global energy minimum. Alternative procedures for generating perturbed conformations to sample the conformational space were also included. These procedures enhance the efficiency of the method by generating a larger number of low-energy conformations. The improved EDMC method has been used to explore the conformational space of a 20-residue polypeptide chain whose sequence corresponds to the membrane-bound portion of melittin. The ECEPP/3 (Empirical Conformational Energy Program for Peptides) algorithm was used to describe the conformational energy of the chain. After an exhaustive search involving 14 independent runs, the lowest energy conformation (LEC) (-91.0 kcal/mol) of the entire study was encountered in four of the runs, while conformations higher in energy by no more than 1.8 kcal/mol were found in the remaining runs with the exception of one of them (run 8). The LEC is identical to the conformation found recently by J. Lee, H. A. Scheraga, and S. Rackovsky [(1988) "Conformational Analysis of the 20-Residue Membrane-Bound Portion of Melittin by Conformational Space Annealing," Biopolymers, Vol. 46, pp. 103-115] as the lowest energy conformation obtained in their study using the conformational space annealing method. These results suggest that this conformation corresponds to the global energy minimum of the ECEPP/3 potential function for this specific sequence: it also appears to be the conformation of lowest free energy.

Amino Acid Sequence↗
PubMed1998

Characterization of fluorescein-oligonucleotide conjugates and measurement of local electrostatic potential.

The properties of fluorescein are substantially altered upon conjugation to nucleic acids, affecting not only the molar absorptivities and fluorescence quantum yields but also the protolytic equilibrium constant and fluorescence lifetimes. Around neutral pH, the fluorescein moiety is present as both mono- and dianion, and the pKa relating them is increased from 6.43 for free fluorescein to about 6.90 for fluorescein attached to both single- and double-stranded oligonucleotides of at least 12 bases/base pairs. This difference reflects the local electrostatic potential around the nucleic acid, which is calculated to -28 mV. The molar absorptivities and spectral responses of the conjugated fluorescein protolytic species are also determined, from which the concentrations of fluorescein-oligonucleotide conjugates can be calculated by assuming: epsilon 494 = 62000/[1 + 10-(pH-6.90)] + 12000/[1 + 10(pH-6.90)] (M-1 cm-1). The fluorescence quantum yield of the conjugates depends, in a complex way, on temperature, environment and oligonucleotide length, sequence and conformation, and must be determined for each experimental situation.

Fluoresceins↗
PubMed1982

Embryotoxic and teratogenic effects of aqueous extracts of tar from a coal gasification electrostatic precipitator.

Aqueous extracts of tar from a coal gasification electrostatic precipitator were tested for its toxic and teratogenic potential in vitro on embryos of the amphibian Xenopus laevis. The 96-h LC50 and EC50 were determined to be 0.83% and 0.48%, respectively. The developmental stage of normal-appearing exposed embryos is not affected by increasing concentrations of the extract. Embryo growth, however, is significantly reduced at concentrations as low as 0.25%. Motility and pigmentation were effectively reduced relative to controls by extract concentrations of 0.5% and greater. Exposed embryos are shorter and stockier than controls. Malformations of head, eyes, viscera, and spine are common, and cartilage formation is abnormal. The epidermis is often hyperplastic, and large blisters occur over the somatic surface. The severity of abnormal development is directly related to the concentration of the toxicant to which the embryos are exposed. Chemical analysis shows that the aqueous extracts contain phenols, furans, monoaromatic and diaromatic hydrocarbons, and mono- and diazaarenes and/or monoaromatic amines.

Abnormalities, Drug-Induced↗
PubMed2002

Method for immobilization of liposomes in capillary electrophoresis by electrostatic interaction with derivatized agarose.

A novel procedure for immobilization of liposomes inside fused-silica capillaries is demonstrated. First, the inner wall of the capillaries was coated with a positively charged polymer, composed of derivatized agarose. Subsequently, negatively charged liposomes were immobilized by electrostatic interaction on the polymer coating. The developed liposome coated capillaries were used as a nanoseparation tool for studying interactions between small drug compounds and liposomes. Part of this work was presented at the 15th International Symposium on Microscale Separations and Analysis, HPCE 2002, Stockholm, Sweden, April 2002.

Electrophoresis, Agar Gel↗
PubMed2003

The dominant interaction between peptide and urea is electrostatic in nature: a molecular dynamics simulation study.

The conformational equilibrium of a blocked valine peptide in water and aqueous urea solution is studied using molecular dynamics simulations. Pair correlation functions indicate enhanced concentration of urea near the peptide. Stronger hydrogen bonding of urea-peptide compared to water-peptide is observed with preference for helical conformation. The potential of mean force, computed using umbrella sampling, shows only small differences between urea and water solvation that are difficult to quantify. The changes in solvent structure around the peptide are explained by favorable electrostatic interactions (hydrogen bonds) of urea with the peptide backbone. There is no evidence for significant changes in hydrophobic interactions in the two conformations of the peptide in urea solution. Our simulations suggest that urea denatures proteins by preferentially forming hydrogen bonds to the peptide backbone, reducing the barrier for exposing protein residues to the solvent, and reaching the unfolded state.

Computer Simulation↗
PubMed2003

Surprising roles of electrostatic interactions in DNA-ligand complexes.

The positions of cations in x-ray structures are modulated by sequence, conformation, and ligand interactions. The goal here is to use x-ray diffraction to help resolve structural and thermodynamic roles of specifically localized cations in DNA-anthracycline complexes. We describe a 1.34 A resolution structure of a CGATCG(2)-adriamycin(2) complex obtained from crystals grown in the presence of thallium (I) ions. Tl(+) can substitute for biological monovalent cations, but is readily detected by distinctive x-ray scattering, obviating analysis of subtle differences in coordination geometry and x-ray scattering of water, sodium, potassium, and ammonium. Six localized Tl(+) sites are observable adjacent to each CGATCG(2)-adriamycin(2) complex. Each of these localized monovalent cations are found within the G-tract major groove of the intercalated DNA-drug complex. Adriamycin appears to be designed by nature to interact favorably with the electrostatic landscape of DNA, and to conserve the distribution of localized cationic charge. Localized inorganic cations in the major groove are conserved upon binding of adriamycin. In the minor groove, inorganic cations are substituted by a cationic functional group of adriamycin. This partitioning of cationic charge by adriamycin into the major groove of CG base pairs and the minor groove of AT base pairs may be a general feature of sequence-specific DNA-small molecule interactions and a potentially useful important factor in ligand design.

Antibiotics, Antineoplastic↗
PubMed2003

Comparison of the conformation and electrostatic surface properties of magainin peptides bound to sodium dodecyl sulfate and dodecylphosphocholine micelles.

The role played by noncovalent interactions in inducing a stable secondary structure onto the sodium dodecyl sulfate (SDS) and dodecylphosphocholine (DPC) micelle-bound conformations of (Ala(8,13,18))magainin 2 amide and the DPC micelle bound conformation of magainin 1 were determined. Two-dimensional NMR and molecular modeling investigations indicated that (Ala(8,13,18))magainin 2 amide bound to DPC micelles adopts a alpha-helical secondary structure involving residues 2-16. The four C-terminal residues converge to a lose beta-turn structure. (Ala(8,13,18))magainin 2 amide bound to SDS miscelles adopts a alpha-helical secondary structure involving residues 7-18. The C- and N-terminal residues exhibited a great deal of conformational flexibility. Magainin 1 bound to DPC micelles adopts a alpha-helical secondary structure involving residues 4-19. The C-terminal residues converge to a lose beta-turn structure. The results of this investigation indicate hydrophobic interactions are the major contributors to stabilizing the induced helical structure of the micelle-bound peptides. Electrostatic interactions between the polar head groups of the micelle and the cationic side chains of the peptides define the positions along the peptide backbone where the helical structures begin and end.

Amino Acid Sequence↗
PubMed2003

Comments on selected aspects of nucleic acid electrostatics.

Recent experimental, theoretical, and computational developments in the field of nucleic acid electrostatics have brought interesting concepts to the fore. The phosphate charge on the double helix apparently influences its structure. When the charge is neutralized asymmetrically, the resulting force imbalance drives bending toward the neutralized side. When the charge is uniformly neutralized, the force imbalance acts to buckle the helical axis, resulting in a compact tertiary conformation. Sharing of condensed counterions by single strands is a stabilizing factor for formation of the double helix. Sharing of condensed counterions by two double helices causes clustering of DNA and may be a factor in RNA folding. Support for these statements is reviewed.

Computer Simulation↗
PubMedDate not supplied

pH dependence of heme electrochemistry in cytochromes investigated by multiconformation continuum electrostatic calculations.

Cytochromes belong to a diverse family of heme-containing redox proteins that function as intermediaries in electron transfer chains. They can be soluble, extrinsic, or intrinsic membrane proteins, and are found in different structural motifs (globin, 4-helix bundles, alpha beta roll, beta sandwich). Measured electrochemical midpoint potentials vary over a wide range even though the basic redox reaction at the heme is the same for all cytochromes. The perturbation of the heme electrochemistry is induced by the protein structure. Also, the pH dependence varies since it depends on the strength of interaction between the heme and surrounding residues as well as the ionization states of these groups. Multiconformation continuum electrostatics (MCCE) has been used to investigate the pH dependence of heme electrochemistry in cytochromes with different folds. Often propionates are the primary contributors for pH dependence especially if they are partially protonated in the reduced heme as it is shown for globin cytochrome c551 P. aeruginosa and cytochrome b5 R. norvegicus (alpha beta roll). However, if the propionates are already fully ionized at a certain pH they do not contribute to the pH dependence even if they have big interaction with the heme. At pH 7 there is no propionate contribution for cytochrome f C. reinhardtii (beta sandwich) and the 4-helix bundle c' R. palustris. Other residues can also change their ionization significantly during heme oxidation and therefore be involved in proton release and pH dependence. These residues have been identified for different cytochrome types.

Amino Acid Motifs↗