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PubMed1994

Molecular dynamics studies on mutants of Cu,Zn superoxide dismutase: the functional role of charged residues in the electrostatic loop VII.

Molecular dynamics (MD) calculations have been performed on mutants of superoxide dismutase (SOD) on some residues present in the electrostatic loop. These calculations have provided the solution structures for the mutants Thr-137-->Ile and Arg; Lys-136-->Ala; Glu-132-->Gln; Glu-133-->Gln; Glu-132, Glu-133-->Gln-132, Gln-133 and-->Gln-132, Lys-133. The structural and dynamic properties of these mutants have been correlated with the catalytic properties and available spectroscopic data. The water molecule present in the active site close to the copper ion in wild type (WT) SOD is missing in the MD average structure of the Thr-137-->Ile mutant, while this molecule is present in the MD average structures of all the other mutants and of WT SOD. This agrees with the experimental data. This is an important result that shows the validity of our calculations and their ability to reproduce even subtle structural features. Addition of one or more positive charges on the 132 and/or 133 positions does not sizably perturb the structure of the active site channel, while the introduction of a positively charged residue (Arg) on position 137 has a large effect on the structure of the electrostatic loop. Analysis of the MD average structures of these mutants has pointed out that the simple electrostatic effects of charged residues in the channel are not the only factor relevant for enzymatic behavior but that the structure of the electrostatic loop and the location of the charged residues also contribute to the catalytic properties of SOD.

Binding Sites↗

PubMed1994

Comparison of electron transfer kinetics between redox proteins free in solution and electrostatically complexed to a lipid bilayer membrane.

The second-order rate constants obtained in solution for the reduction of horse cytochrome c (cytc; net charge +7) by either Clostridium beijerinckii flavodoxin semiquinone (Fld; net charge -16) or reduced spinach ferredoxin (Fd; net charge -15) decrease monotonically with increasing ionic strength, as expected for reactions between oppositely charged species. Although the rate constant for the Fld reaction is almost two orders of magnitude larger at low ionic strength than that for Fd, the values extrapolated to infinite ionic strength are closely similar, indicating comparable reactivities when electrostatic effects are eliminated. Furthermore, Fld has a much larger value for the electrostatic interaction energy, and thus a larger apparent active site charge, than does Fd, accounting for the rate constant disparity at low ionic strength. Electrostatically binding cytc at low ionic strength to a negatively charged lipid bilayer vesicle (membranes containing mixtures of egg phosphatidylcholine (PC) and cardiolipin (CL)) results in a marked decrease of the observed electron transfer rate constant (k(obs)) for reduction of the cytochrome by both Fld and Fd. The magnitude of this decrease is proportional to the mole percent of CL present in the membrane (10- to 20-fold change over 5-60 mol%). With Fld, k(obs) decreases monotonically with increasing ionic strength at a fixed CL concentration. With Fd an increase in k(obs) occurs as the ionic strength is increased, which maximizes at intermediate ionic strength at a value larger than that obtained in the absence of lipid vesicles. When Fld is electrostatically bound to a positively charged vesicle composed of 40 mol% dioctadecyldimethylammonium ion (DODAC) and 60 mol% PC, again k(obs) for electron transfer to cytc is decreased over that obtained in solution, and the magnitude is diminished monotonically by increasing ionic strength. In contrast, k(obs) for electron transfer from Fd to cytc is unaffected by the presence of the positively charged membrane. The implications of these results for the role of membrane surface charge in modulating protein-protein interactions is discussed.

Cardiolipins↗

PubMed1998

Electrostatic Interaction and Hindered Diffusion of Ion-Penetrable Spheres in a Slit Pore.

Electrostatic interaction and hindered diffusion of ion-penetrable spheres in a slit pore filled with an electrolyte solution are investigated theoretically. The concentration of the particles is assumed sufficiently low so that the interactions between the particles can be neglected. The slit pore comprises two parallel infinite plates, which can be either permeable or impermeable to the electrolyte. The electrostatic interaction energy is obtained analytically by adopting an integral of Green's function and an image method. It is found that for impermeable plates having constant surface charge densities, the electrostatic interaction can be attractive or repulsive for a particle with charge of opposite sign, depending on the relative magnitudes of charge densities and particle location. Similar behavior is predicted for plates with constant surface potential and a particle with charge of like sign. The interaction energy is used to determine the spatial distribution of the particle in the pore and the partition coefficient, and then to calculate the average and apparent diffusivities. The average diffusivity calculated from the average mobility in the pore is always smaller than that in the bulk solution because of greater drag the particle experiences in the presence of the plates. This mean diffusivity is larger than that in the corresponding neutral system for repulsive electrostatic interaction, but becomes smaller for attractive interaction. The apparent diffusivity defined from the flux based on the bulk concentration of the particle depends strongly on the ion concentration, as does the partition coefficient when the double layer is sufficiently thick. Copyright 1998 Academic Press.

Journal Article↗

PubMed1995

Preferential heterodimeric parallel coiled-coil formation by synthetic Max and c-Myc leucine zippers: a description of putative electrostatic interactions responsible for the specificity of heterodimerization.

The oncoprotein c-Myc must heterodimerize with Max to bind DNA and perform its oncogenic activity. The c-Myc-Max heterodimer binds DNA through a basic helix-loop-helix leucine zipper (b-HLH-zip) motif and it is proposed that leucine zipper domains could, in concert with the HLH regions, provide the specificity and stability of the b-HLH-zip motif. In this context, we have synthesized the peptides corresponding to the leucine zipper domains of Max and c-Myc with a N-terminal Cys-Gly-Gly linker and studied their dimerization behavior using reversed-phase HPLC and CD spectroscopy. The preferential formation of a fully helical parallel c-Myc-Max heterodimeric coiled-coil was observed under air-oxidation and redox conditions at neutral pH. We show that the stability and the helicity of the disulfide-linked c-Myc-Max heterostranded coiled-coil is modulated by pH, with a maximum around pH 4.5, supporting the existence of stabilizing and specific interhelical electrostatic interactions. We present a molecular model of the c-Myc-Max heterostranded coiled-coil describing potential electrostatic interactions responsible for the specificity of the interaction, the main feature being putative buried electrostatic interactions between a histidine side-chain (in the Max leucine zipper) and two glutamic acid side-chains (in the c-Myc leucine zipper) at the heterodimer interface. This model is supported by the fact that the apparent pKa (as determined by [1H]-NMR spectroscopy) of this histidine side-chain at 25 degrees C is 0.42 (+/- 0.05) pKa units higher in the folded form than in the unfolded form. This indicates that the charged histidine side-chain contributes approximately 0.57 (+/- 0.07) kcal/mol (2.38 (+/- 0.30) kJ/mol) of stabilization free energy to the c-Myc-Max heterostranded coiled-coil through favorable electrostatic interaction.

Amino Acid Sequence↗

PubMed2002

Electrostatics significantly affect the stability of designed homeodomain variants.

The role of electrostatic interactions in determining the stability of designed proteins was studied by constructing and analyzing a set of designed variants of the Drosophila engrailed homeodomain. Computational redesign of 29 surface positions results in a 25-fold mutant with moderate stability, similar to the wild-type protein. Incorporating helix dipole and N-capping considerations into the design algorithm by restricting amino acid composition at the helix termini and N-capping positions yields a ninefold mutant of the initial design (a 23-fold mutant of wild-type) that is over 3 kcal mol(-1) more stable than the protein resulting from the unbiased design. Four additional proteins were constructed and analyzed to isolate the effects of helix dipole and N-capping interactions in each helix. Based on the results of urea-denaturation experiments and calculations using the finite difference Poisson-Boltzmann method, both classes of interaction are found to increase the stability of the designed proteins significantly. The simple electrostatic model used in the optimization of rotamers by iterative techniques (ORBIT) force-field, which is similar to the electrostatic models used in other protein design force-fields, is unable to predict the experimentally determined stabilities of the designed variants. The helix dipole and N-capping restrictions provide a simple but effective method to incorporate two types of electrostatic interactions that impact protein stability significantly.

Algorithms↗

PubMed1994

Electrostatic complementarity between proteins and ligands. 2. Ligand moieties.

Drug design strategies consider factors governing intermolecular interactions to build up putative ligands. In many strategies, the ligand is constructed using fragments which are placed in the site sequentially. The optimization is then performed with each fragment. We would like to examine if this optimization strategy could generate ligands with optimal electrostatic interactions. The electrostatic complementarities between constituent moieties and the receptor site have been calculated. The whole-ligand complementarity does not appear to be the mathematical mean of the individual complementarities, nor have we found a simple relationship between the moiety and whole-ligand complementarities. The results demonstrate clearly that, using a simple model, it is very difficult to predict the electrostatic potential complementarity of the whole ligand from the complementarities of its constituent chemical moieties. This means that ligand design strategies must optimize the electrostatic complementarity globally, and not moiety by moiety.

4-Hydroxybenzoate-3-Monooxygenase↗

PubMed1996

On the electrostatic and steric similarity of lactam compounds and the natural substrate for bacterial cell-wall biosynthesis.

Electrostatic and structural properties of a set of beta-lactam, gamma-lactam and nonlactam compounds have been analyzed and compared with those of a model of the natural substrate D-alanyl-D-alanine for the carboxy- and transpeptidase enzymes. This first comparison of the electrostatic properties has been based on a distributed multipole analysis of high-quality ab initio wave functions of the substrate and potential antibiotics. The electrostatic similarity of the substrate and active compounds is apparent, and contrasts with the electrostatic properties of the noninhibitors. This has been quantified to give a reasonable correlation with the MIC (Minimum Concentration for Inhibition) and with kinetic data (k2/K) in accordance with the model for interaction of the lactam compounds with DD-peptidase. These correlations provide a better prediction of antibacterial activity than purely structural criteria.

Amino Acid Sequence↗

PubMed1989

The multiple-minima problem in the conformational analysis of polypeptides. III. An electrostatically driven Monte Carlo method: tests on enkephalin.

The three-dimensional conformation of Met-enkephalin, corresponding to the lowest minimum of the empirical potential energy function ECEPP/2 (empirical conformational energy program for peptides), has been determined using a new algorithm, viz. the Electrostatically Driven Monte Carlo Method. This methodology assumes that a polypeptide or protein molecule is driven toward the native structure by the combined action of electrostatic interactions and stochastic conformational changes associated with thermal movements. These features are included in the algorithm that produces a Monte Carlo search in the conformational hyperspace of the polypeptide, using electrostatic predictions and a random sampling technique to locate low-energy conformations. In addition, we have incorporated an alternative mechanism that allows the structure to escape from some conformational regions representing metastable local energy minima and even from regions of the conformational space with great stability. In 33 test calculations on Met-enkephalin, starting from arbitrary or completely random conformations, the structure corresponding to the global energy minimum was found in all the cases analyzed, with a relatively small search of the conformational space. Some of these starting conformations were right or left-handed alpha-helices, characterized by good electrostatic interactions involving their backbone peptide dipoles; nevertheless, the procedure was able to convert such locally stable structures to the global-minimum conformation.

Electrochemistry↗

PubMed1998

Electrostatic charge characteristics of Der p1 allergen-carrying particles and the house dust mite dermatophagoides pteronyssinus.

Control of the house dust mite allergen has received considerable attention owing to its importance in some allergic diseases. One aspect of dust mites and their allergen-carrying faecal particles that has not been reported on, which may have allergen control applications, is the electrostatic charge they carry in the natural environment. To promote tribo-electric charging, household dust containing dust mite allergen and live house dust mites are separately agitated while in contact with either polypropylene, nylon or earthed metal. The charged dust and mites are subsequently subjected to electrostatic separation and collection. Results for concentrations of the house dust mite allergen, Der p1, indicate that, when subjected to nylon, Der p1 carrier particles appear to be predominantly positively charged. Similarly, when subjected to polypropylene, Der p1 carrier particles also appear to be positively charged. Reduction of excess free charge by agitation against earthed metal does not appear to affect the observed charging characteristics, indicating that the positive charge may be bound or inherent in the Der p1 carrier particles. In contrast, house dust mites exposed to nylon appear to be generally charging negative, whereas mites exposed to polypropylene appear to be charging positive. The observed electrostatic characteristics of the mites and Der p1 carrying particles will be useful in the future development of electrostatic allergen control methods.

Allergens↗

PubMed2005

Electrostatics of Cytochrome-c assemblies.

Electrostatic potentials along with computational mutagenesis are used to obtain atomic level insights into Cytochrome-c in order to design efficient bionanosensors. The electrostatic properties of wild type and mutant Cytochrome-c are examined in the context of their assembly, i.e. are examined in the absence and presence of neighboring molecules from the assembly. An intense increase in the positive potential ensues when the neighboring molecules are taken into account. This suggests that in the extrapolation of electric field effects upon the design of assemblies, considering the properties of only the central molecule may not be sufficient. Additionally, the influence of the uncharged residues becomes quite diminished when the molecule is considered in an assembly. This could pave the way for making mutants that might be more soluble in different media used in the construction of devices. [Figure: see text]. The electrostatic potential, calculated using the program DELPHI mapped on to the surface of Cytochrome-c when it is considered by itself (in the left column) and in the presence of the electrostatic field generated by the presence of the surrounding 4 molecules on the right. The potentials range from -10kT in red to +10kT in blue. The central figure shows the regions that have been mutated to positively charged residues by placing a unit positive charge at the terminal atom of the respective side chain. The figures range from the wild type in the first row, followed by the Gln12, Asn70, Asp50, Glu90 and Ala83 mutants.

Cytochromes c↗

PubMed2005

Novel deposition of nano-sized silicon substituted hydroxyapatite by electrostatic spraying.

Suspensions containing nano-sized silicon substituted hydroxyaptite (nSiHA) particles were produced and processed for electrostatic spray deposition. No secondary phases were detected by X-ray diffraction, which indicated that the nSiHA was phase pure. Electrostatic spraying of nSiHA in cone-jet mode was achieved at flow rate of 10(-9) m3s(-1) with an applied voltage between the needle and the ring-shaped ground electrode set at 6 to 8 kV. Micrometer- and submicrometer-scaled islands of nSiHA have been deposited on glass and titanium substrates. The surface roughness of such nHA and nSiHA islands was in the range 60 to 80 nm, as measured from atomic force microscopy in tapping mode. The growth of primary human osteoblast (HOB) cells on the nSiHA deposited substrates increased with time during the 4 days of culture, and the increase was related with the Si content in substituted HA, indicating that nSiHA was able to promote and support the growth of HOB cells. Scanning electron microscopy (SEM) revealed that extracellular matrix (ECM) produced by the HOB cells on these nSiHA deposits was well organized. In addition, the presence of Ca and P containing nodules in the ECM were also confirmed by Energy Dispersive X-ray (EDX) analysis, indicating early signs of calcification fronts. The results showed that nSiHA produced by electrostatic spray deposition was able to promote the attachment and the growth of HOB cells. Therefore, electrostatic spray deposition offers great potential for the creation of bioactive surfaces to provide improved interfacial bonding with host tissues.

Cell Adhesion↗

PubMed1991

Laser flash photolysis studies of the kinetics of reduction of ferredoxins and ferredoxin-NADP+ reductases from Anabaena PCC 7119 and spinach: electrostatic effects on intracomplex electron transfer.

The influence of electrostatic forces on the formation of, and electron transfer within, transient complexes between redox proteins was examined by comparing ionic strength effects on the kinetics of the electron transfer reaction between reduced ferredoxins (Fd) and oxidized ferredoxin-NADP+ reductases (FNR) from Anabaena and from spinach, using laser flash photolysis techniques. With the Anabaena proteins, direct reduction by laser-generated flavin semiquinone of the FNR component was inhibited by complex formation at low ionic strength, whereas Fd reduction was not. The opposite results were obtained with the spinach system. These observations clearly indicate structural differences between the cyanobacterial and higher plant complexes. For the complex formed by the Anabaena proteins, the results indicate that electrostatic forces are not a major contributor to complex stability. However, the rate constant for intracomplex electron transfer had a biphasic dependence on ionic strength, suggesting that structural rearrangements within the transient complex facilitate electron transfer. In contrast to the Anabaena complex, electrostatic forces are important for the stabilization of the spinach Fd:FNR complex, and changes in ionic strength had little effect on the limiting rate constant for intracomplex electron transfer. This suggests that in this case the geometry of the initial collisional complex is optimal for reaction. These results provide a clear illustration of the differing roles that electrostatic interactions may play in controlling electron transfer between two redox proteins.

Cyanobacteria↗

PubMed1981

Electrostatic control by lipids upon the membrane-bound (Na+ + K+)-ATPase.

In this paper, the membrane-bound (Na+ + K+)-ATPase from bovine brain is shown to be controlled by electrostatic alterations of the charged lipids surrounding the enzyme. The properties under investigation are the enzymatic activity, activation energy and the response of the enzymatic system to temperature. Arrhenius plots of the ATPase activity are biphasic with a break at temperature Ti. The temperature Ti, the activation energies at temperatures above and below Ti, and the enzymatic activity at any constant temperature have been shown to depend upon the concentrations of alkali and alkaline-earth metal ions in the solution. These electrolyte dependencies are ascribed to changes of electrostatic conditions at the lipids surrounding the ATPase. If the higher electrostatic screening ability of divalent ions is taken into account, the results in the presence of mono- and divalent ions become virtually the same. As a result of this work, it is concluded that electrostatic alterations are transmitted to the ATPase from the lipids of the membrane in which the enzyme is embedded. Inhibition and activation of the enzyme by mono-and divalent metal ions may thus be explained without any auxiliary hypothesis, particularly without postulating specific binding sites for the different ionic species at the protein. In addition, the specific lipid requirement of the ATPase may be understood better in the light of this interpretation.

Animals↗

PubMed1987

Electrostatic effects and hydrogen exchange behaviour in proteins. The pH dependence of exchange rates in lysozyme.

The pH dependence of the exchange rates for a number of tryptophan and amide hydrogen atoms in hen egg-white lysozyme has been determined at temperatures well below the thermal denaturation temperature. The pH behaviour of each hydrogen is unique and can differ markedly from that of simple compounds. A model for electrostatic effects in proteins is described and used to explain a number of the features of the pH dependence of the exchange rates of certain hydrogens. The results indicate that exchange takes place from a conformation of the protein closely similar to that of the native protein, with local fluctuations providing the mechanism for exchange. For the more-buried hydrogens at low pH values there is a general increase in the exchange rates caused by the decreasing stability of the protein as calculated from the electrostatic model. The analysis shows how evidence from hydrogen exchange studies can be used to provide information about electrostatic interactions in localized regions of proteins. A description of the electrostatic model and some applications are given in the Appendix.

Amino Acid Sequence↗

PubMed1990

Electrostatic mechanism of chromatin folding.

We describe a theoretical analysis of cation binding in the nucleosome, and in chromatin as it folds, using Manning's polyelectrolyte theory. The theory accounts remarkably well, even quantitatively, both for the interaction of histone charges with DNA in chromatin, and for the essential features of the folding process. The degree of chromatin folding under different ion conditions is reliably predicted by the electrostatic free energy of DNA in the H1 binding site, which determines repulsions between linker DNA segments thus limiting how closely they may approach. The electrostatic free energy is a function of the ionic strength and the residual (unneutralized) DNA charge. Monovalent cations effect chromatin folding primarily by screening the residual charge whilst divalent or trivalent cations bind to DNA reducing its residual charge. The binding of H1 to the linker DNA considerably reduces its electrostatic free energy by displacing bound cations and reducing the residual charge. Thus, native chromatin folds at lower salt concentrations than does H1-depleted chromatin. We conclude that the mechanism of chromatin folding is primarily electrostatic in nature. In vivo ion conditions are such that chromatin is compact but H1 molecules are able to exchange freely, probably due to a low degree of salt-induced dissociation. When H1 molecules exchange, transient local disruptions may occur in the chromatin filament due to repulsion of temporarily H1-free linker DNA from within the filament, such that chromatin "breathes". Thus, the cell can maintain its chromatin in a compact form and access to DNA for sequence-specific DNA-binding proteins and the transcription machinery is still possible.

Animals↗

PubMed1996

Characterization of pyridoxal phosphate as an optical label for measuring electrostatic potentials in proteins.

This paper presents data which allow one to characterize pyridoxal 5'-phosphate (PLP) as an optical label for electrostatic potential measurements in proteins. Experimental studies were carried out with 6-N-(5'-phosphopyridoxyl)-2-N-acetyl-lysyl methyl ester (PLP-ALME) as a model compound which simulates PLP covalently bound to a protein. Calculations of electrostatic potential maps were done using the model compound 2,4-dimethyl-3-hydroxy-5-hydroxymethyl phosphate-pyridine (DHHPP). Studies on relative changes in PLP-ALME fluorescence and absorbance vs. pH resulted in four pKa values of PLP-ALME in solution which can be used as intrinsic pKa values (pKint) of the ionizable groups of the label covalently bound to the protein. The pKa values obtained from fluorescence data are 4.1, 5.6, 8.7 and 11.1 and those from absorbance data are 3.1, 4.7, 8.7 and 11.0. The differences between corresponding pKa values are related to differences in PLP-ALME behaviour between the excited and ground electronic states and to intramolecular charge-charge interactions. Quenching of PLP-ALME fluorescence by I-, acrylamide and Cs+ at pH 6, 7 and 8 shows that in the case of I- and acrylamide the Stern-Volmer constants of quenching (Ksv) decrease with increasing pH, while the opposite is true for Ksv of Cs+. These results as well as the analysis of electrostatic potential maps of DHHPP show that with its ampholytic character PLP can be used to measure local electrostatic potentials in the pH range 5-9.

Acrylamide↗

PubMed2006

A theoretical elucidation of bilirubin interaction with HSA's lysines: first electrostatic binding site in IIA subdomain.

The electrostatic interaction of amino acid lysines 190, 195 and 199 of human serum albumin (HSA) with bilirubin have been investigated using molecular dynamic simulations, QM and QM/MM minimization methods. In this study two methodological approaches have been employed. In the first approach X-ray structure and the structure obtained from the molecular dynamic simulation of subdomain IIA of HSA in vacuum have been utilized. Interactions have been evaluated with the segment 186-200 of the cited subdomain. Calculations on the X-ray structure of above segment indicate an effective interaction of the lysine 195 with bilirubin, although that of the lysine 190 is also found considerable in this structure. Performing simulation in vacuum, it has been revealed that except for the lysine 195, the other two lysine residues (190 and 199) could not be considered as centers of interaction. Such finding, which is in accord with experimental data, lends support to the procedure employed in this study. NBO analyses suggest that tasks to achieve a structure indicating bilirubin interaction with the lysine 195 from the 186-200 segment extracted from X-ray structure, results in a structure that lacks any electrostatic interaction. In fact, it has been found that the stability of the latter species can be attributed to the H-bonding interaction of the glutamate 188 with both bilirubin and the lysine 195. Further NBO analysis on the structure of the same species, while achieved after molecular dynamic simulation on subdomain IIA in vacuum has revealed that a favorable electrostatic interaction between the lysine 195 and bilirubin has occurred. Besides, H-bonding interaction of the glutamate 188 with bilirubin has been evident in the same species. For the second approach, presence of water molecules and ions has been considered to simulate condensed medium. Applying docking, conformational sampling, and QM/MM minimization steps in sequence, a structure has been achieved which presents a specific interaction between epsilon-NH3(+) group of the lysine 195 residue and the lactam oxygen atom of bilirubin. NBO analyses suggest that above electrostatic interaction is combined with hydrogen bonding interaction between same two groups. Moreover, a hydrogen bond between oxygen atom of bilirubin's acetate group and alpha-NH group of lysine 195 has been observed. Molecular orbital calculations have been presented which support the NBO analyses.

Bilirubin↗

PubMed2004

Electrostatic interactions in protein adsorption probed by comparing lysozyme and succinylated lysozyme.

The influence of electrostatic interactions on protein adsorption was studied by comparing the adsorption of lysozyme and succinylated lysozyme at silica surfaces. The succinylation affects the charge of the protein, but also the stability. Although changes in stability can have an influence on adsorption, our data show that the primary effect can be entirely understood in terms of electrostatic interactions. The adsorbed amount as a function of pH has a maximum for both proteins. This maximum coincides with the isoelectric point for succinylated lysozyme, and is close to the isoelectric point for lysozyme. At pH values where the protein is electrostatically repelled by the sorbent, higher ionic strengths increase adsorption, and for electrostatic attraction higher ionic strengths decrease adsorption.

Adsorption↗