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PubMed2000

Structural alignment of ferredoxin and flavodoxin based on electrostatic potentials: implications for their interactions with photosystem I and ferredoxin-NADP reductase.

The two proteins ferredoxin and flavodoxin can replace each other in the photosynthetic electron transfer chain of cyanobacteria and algae. However, structure, size, and composition of ferredoxin and flavodoxin are completely different. Ferredoxin is a small iron-sulfur protein (approximately 100 amino acids), whereas flavodoxin is a flavin-containing protein (approximately 170 amino acids). The crystal structure of both proteins from the cyanobacteria Anabeana PCC 7120 is known. We used these two protein structures to investigate the structural basis of their functional equivalence. We apply the Hodgkin index to quantify the similarity of their electrostatic potentials. The technique has been applied successfully in indirect drug design for the alignment of small molecule and bioisosterism elucidation. It requires no predefined atom-atom correspondences. As is known from experiments, electrostatic interactions are most important for the association of ferredoxin and flavodoxin with their reaction partners photosystem I and ferredoxin-NADP reductase. Therefore, use of electrostatic potentials for the structural alignment is well justified. Our extensive search of the alignment space reveals two alignments with a high degree of similarity in the electrostatic potential. In both alignments, ferredoxin overlaps completely with flavodoxin. The active sites of ferredoxin and flavodoxin rather than their centers of mass coincide in both alignments. This is in agreement with electron microscopy investigations on photosystem I cross-linked to ferredoxin or flavodoxin. We identify residues that may have the same function in both proteins and relate our results to previous experimental data.

Algal Proteins↗
PubMed2004

Rational redesign of inhibitors of furin/kexin processing proteases by electrostatic mutations.

AIM: To model the three-dimensional structure and investigate the interaction mechanism of the proprotein convertase furin/kexin and their inhibitors (eglin c mutants). METHODS: The three-dimensional complex structures of furin/kexin with its inhibitors, eglin c mutants, were generated by modeller program using the newly published X-ray crystallographical structures of mouse furin and yeast kexin as templates. The electrostatic interaction energy of each complex was calculated and the results were compared with the experimentally determined inhibition constants to find the correlation between them. RESULTS: High quality models of furin/kexin-eglin c mutants were obtained and used for calculation of the electrostatic interaction energies between the proteases and their inhibitors. The calculated electrostatic energies of interaction showed a linear correlation to the experimental inhibition constants. CONCLUSION: The modeled structures give good explanations of the specificity of eglin c mutants to furin/kexin. The electrostatic interactions play important roles in inhibitory activity of eglin c mutants to furin/kexin. The results presented here provided quantitative structural and functional information concerning the role of the charge-charge interactions in the binding of furin/kexin and their inhibitors.

Animals↗
PubMed2005

Electrostatic potentials of E.coli genome DNA.

Distribution of electrostatic potential of the complete sequence of E. coli genome was calculated. Comparative analysis of electrostatic patterns for 359 promoter and nonpromoter nucleotide sequences was carried out. It is found that nonpromoter regions are characterized by more homogeneous distribution of electrostatic potential with no common specific elements. Electrostatic patterns of promoter DNAs can be specified due to the presence of some distinctive motifs which may be involved as promoter signal elements in RNA-polymerase-promoter recognition.

Base Sequence↗
PubMedDate not supplied

[Theoretical studies of the electrostatic interactions in aspartic proteinases, intramolecular interactions in pepsin and penicillopepsin].

A semi-empirical approach has been used to estimate the intramolecular electrostatic interactions in pepsin and penicillopepsin. The pH-dependence of the free energy electrostatic term was calculated, and the pH-dependence of the domain interactions has been estimated. As it was shown, the contribution of electrostatic interactions is rather small for the stabilization of the native structure. At the same time the electrostatic repulsion between domains increases with the increase of pH. The later can be the cause of the alkaline denaturation of pepsin and domain mobility.

Aspartic Acid Endopeptidases↗
PubMed1980

[Relationship between catalytic properties, fixed charge concentration and electrostatic potential of polyelectrolyte-bound enzymes].

An equation for the calculation of the electrostatic potentials of polyelectrolyte-enzyme supports from electrostatic parameters has been derived by relating two different theories which describe the catalytic behaviour of polyelectrolyte-bound enzymes. The electrostatic potentials of polyionic supports have been determined by use of experimental results, on the one hand, from the fixed charge concentration and the ionic strength, on the other hand, from pH- and Km-shifts of immobilized enzymes. The accordance of potentials calculated from electrostatic and kinetic parameters confirms the macroscopic carrier-enzyme model.

Amylases↗
PubMedDate not supplied

[Electrostatic protection from cosmic radiation (the current status and prospects)].

Conduction currents of the vacuum atmosphere near the spacecraft were measured in an electrostatic shielding and an electrostatic shielding module in electrostatic fields of about 10(7) Wt/m at a voltage of 3 X 10(5) V onboard Cosmos-605, 690, 732 and 936. The resultant conduction currents (less than or equal to 10(-9) A/m2) give evidence that the vacuum environment has high electroinsulation properties which contradicts the concepts derived from ground-based studies. Using up-to-date high-voltage devices, it appears possible to develop an efficient electrostatic shielding which will be of a low weight and a low power consumption.

Cosmic Radiation↗
PubMed1994

Electrostatic potential surfaces of the transition state for AMP deaminase and for (R)-coformycin, a transition state inhibitor.

The transition state for the hydrolysis of AMP by AMP deaminase has been characterized by heavy atom kinetic isotope effects (Merkler, D.J., Kline, P.C., Weiss, P., and Schramm, V.L. (1993) Biochemistry 32, 12993-13001). The experimentally established transition state includes a bond order of 0.8 to the attacking water nucleophile, a full bond order to the exocyclic 6-amino group, rehybridization of C-6 of the purine ring to sp3 and protonation of N-1 by Glu633. The transition state is one the path to formation of an unstable tetrahedral intermediate in which the exocyclic amine undergoes rapid protonation followed by its departure. In this mechanism, the highest energetic barrier on the reaction coordinate is the attack of the zinc-activated water. In a further test of this transition state structure, the electrostatic potential surface for the purine ring of the transition state has been determined by molecular orbital calculations and compared to that of the base of (R)-coformycin 5'-monophosphate, a slow onset, tight binding inhibitor of AMP deaminase that binds with an overall dissociation constant of 10(-11) M. The electrostatic potential surfaces of the aglycones of the transition state and (R)-coformycin are compared to the adenine ring of the substrate and to an alternative transition state structure in which the transition state is late, with fully bonded hydroxyl and fully protonated exocyclic amine. The results indicate a near-match of the electrostatic potential surfaces for the early transition state and (R)-coformycin. The electrostatic nature of the late transition state with a protonated amine leaving group differs both from the transition state determine by kinetic isotope effects and from that of (R)-coformycin analogues. The results provide evidence that the nature of the enzyme-stabilized transition state for adenine deamination involves an early transition state with a partially bonded hydroxyl group. The observed tight binding inhibition by (R)-coformycin analogues as transition state inhibitors results from the similarity of the partial charges on the inhibitors to that of the enzymatic transition state stabilized by AMP deaminase.

AMP Deaminase↗
PubMedDate not supplied

Role of the electrostatic attractive force in the adsorption of proteins by aluminum hydroxide adjuvant.

The fact that both aluminum hydroxide adjuvant and proteins have a pH dependent surface charge means that electrostatic forces play a role in the adsorption of proteins by aluminum hydroxide adjuvant during the preparation of vaccines. The objective of this study was to examine the contribution of the electrostatic attractive force in the adsorption of proteins by aluminum hydroxide adjuvant. Since the surface charge characteristics of aluminum hydroxide adjuvant can be modified by the adsorption of phosphate anion, a series of aluminum hydroxide adjuvants were prepared by treatment with various concentrations of phosphate anion. The isoelectric points (iep) of these adjuvants ranged from 11.0 to 4.6 and the electrophoretic mobilities at pH 7.4 ranged from 2.0 to -3.3 microns cm/V s. The line broadening of the (020) band of the X-ray diffraction pattern indicated that treatment with phosphate anion did not change the primary crystallite dimension. Adsorption at pH 7.4 of positively charged lysozyme (iep = 11.1) was directly related to the negative surface charge of the adjuvant. No adsorption occurred when the surface charge was positive. In contrast, negatively charged ovalbumin (iep = 4.6) was adsorbed by all of the adjuvants at pH 7.4, although the adsorptive capacity was the greatest when the surface charge was positive. The results indicate that adsorptive forces in addition to the electrostatic attractive force play an important role in the adsorption of some proteins by aluminum hydroxide adjuvant. It is believed the structurally flexible proteins, like ovalbumin, exhibit more complex adsorption behavior than structurally rigid proteins, like lysozyme, for which adsorptive behavior can be explained by electrostatic forces.

Adsorption↗
PubMed1977

[Investigations on the effect of an electrostatic field free of residual waves on the motility of the mouse (author's transl)].

Comparative investigations were carried out concerning the influence on the motility of mice of different electrobioclimatic conditions (electrostatic field with a residual wave component of 1% and a field strength of 4.500 V/m; pure residual wave component: 32 Vs/s, field strength 120 V/m/ss; electrostatic field established by batteries: initial voltage 900 V, field strength 4.500 V/m; shielded from ambient atmospheric electrical fields: damping efficiency at 99%). The Faraday condition represented the control as absolutely objective physical magnitude. All experimental chambers were positioned under Faraday shields. Following a 20 day period of acclimatization to the unaccustomed surroundings for the animals (adaptation period), we established the previously described electrophysical conditions in the cages for a further period of 20 days (experimental period). The lowest values measured during the daily readings were found in the Faraday cage, resp. in the pure electrostatic field, the highest in the DC-field with residual wave component resp. in the residual wave component alone. We draw the following conclusion from the findings: the pure DC-field apparently does not possess those bioclimatologically decisive importance that has been and is being postulated from several sides. Many of the stimtng effects observed and attributed to the electrostatic field are most probably due to the residual wave component resulting from the high-voltage generators employed.

Animals↗
PubMed1997

Self-consistent field approach to protein structure and stability. I: pH dependence of electrostatic contribution.

Starting from the simple case of an external field acting on noninteracting particles, a formulation of the self-consistent field theory for treating proteins and unfolded protein chains with multiple interacting titratable groups is given. Electrostatic interactions between the titratable groups are approximated by a Debye-Huckel expression. Amino acid residues are treated as polarizable bodies with a single dielectric constant. Dielectric properties of protein molecules are described in terms of local dielectric constants determined by the space distribution of residue volume density around each ionized residue. Calculations are based on average charges of titratable groups, distance of separation between them, on their pKa's, residue volumes and on the local dielectric constant. A set of different residue volumes is used to analyze the influence of the permanent dipole of polar parts of the residue on calculated titration curves, electrostatic contribution to the free energy of protein stability, and pK shifts. Calculations with zero volumes--which means that charged portions of protein molecules are viewed as part of the high dielectric medium--give good agreement with experimental data. The theory was tested against most accurate approaches currently available for the calculation of the pKa's of ionizable groups based upon finite difference solutions of the Poisson-Boltzmann equation (FDPB). For 70 theoretically calculated pKa's in a total of six proteins the accuracy of the approach presented here is assessed by comparison of computed pKa's with that measured. The overall root-mean-square error is 0.79, compared to the value 0.89 obtained by FDPB approach given in the paper of Antosiewicz et al. (J. Mol. Biol. 238:415-436, 1994). The test of Debye-Huckel approximation for the electrostatic pair interactions shows that it is in excellent agreement with experimental data as well as the calculations of the FDPB and Tanford-Kirkwood methods on the pK shifts of His64 in the active site of subtilisin over the whole range of ionic strengths. (Gilson and Honig, Proteins 3:32-52, 1988; Russell et al., J.Mol.Biol. 193:803-813, 1987). The theory was also analytically and numerically tested on a simple models where the exact statistical mechanical treatment is still simple (Yang et al., Proteins 15:252-265, 1993; Bashford and karplus, J. Phys. Chem. 95:9556-9561, 1991).

Aprotinin↗
PubMed2000

Electrostatic strengths of salt bridges in thermophilic and mesophilic glutamate dehydrogenase monomers.

Here we seek to understand the higher frequency of occurrence of salt bridges in proteins from thermophiles as compared to their mesophile homologs. We focus on glutamate dehydrogenase, owing to the availability of high resolution thermophilic (from Pyrococcus furiosus) and mesophilic (from Clostridium symbiosum) protein structures, the large protein size and the large difference in melting temperatures. We investigate the location, statistics and electrostatic strengths of salt bridges and of their networks within corresponding monomers of the thermophilic and mesophilic enzymes. We find that many of the extra salt bridges which are present in the thermophilic glutamate dehydrogenase monomer but absent in the mesophilic enzyme, form around the active site of the protein. Furthermore, salt bridges in the thermostable glutamate dehydrogenase cluster within the hydrophobic folding units of the monomer, rather than between them. Computation of the electrostatic contribution of salt bridge energies by solving the Poisson equation in a continuum solvent medium, shows that the salt bridges in Pyrococcus furiosus glutamate dehydrogenase are highly stabilizing. In contrast, the salt bridges in the mesophilic Clostridium symbiosum glutamate dehydrogenase are only marginally stabilizing. This is largely the outcome of the difference in the protein environment around the salt bridges in the two proteins. The presence of a larger number of charges, and hence, of salt bridges contributes to an electrostatically more favorable protein energy term. Our results indicate that salt bridges and their networks may have an important role in resisting deformation/unfolding of the protein structure at high temperatures, particularly in critical regions such as around the active site.

Clostridium↗
PubMed2000

Electrostatic properties of bovine beta-lactoglobulin.

Bovine beta-Lactoglobulin (BLG) has been studied for many decades, but only recently structural data have been obtained, making it possible to simulate its molecular properties. In the present study, electrostatic properties of BLG are investigated theoretically using Poisson-Boltzmann calculations and experimentally following pH titration via NMR. Electrostatic properties are determined for several structural models, including an ensemble of NMR structures obtained at low pH. The changes in electrostatic forces upon changes in ionic strength, solvent dielectric constant, and pH are calculated and compared with experiments. pK(a)s are computed for all titratable sites and compared with NMR titration data. The analysis of theoretical and experimental results suggests that (1) there may be more than one binding sites for negatively charged ligands; (2) at low pH the core of the molecule is more compact than observed in the structures obtained via restrained molecular dynamics from NMR data, but loop and terminal regions must be disordered.

Amino Acid Sequence↗
PubMed2001

Rapid boundary element solvation electrostatics calculations in folding simulations: successful folding of a 23-residue peptide.

Solvation effects play a profound role in the energetics of protein folding. While a continuum dielectric model of solvation may provide a sufficiently accurate estimate of the solvation effects, until now this model was too computationally expensive and unstable for folding simulations. Here we proposed a fast yet accurate and robust implementation of the boundary element solution of the Poisson equation, the REBEL algorithm. Using our earlier double-energy scheme, we included for the first time the mathematically rigorous continuous REBEL solvation term in our Biased Probability Monte Carlo (BPMC) simulations of the peptide folding. The free energy of a 23-residue beta beta alpha-peptide was then globally optimized with and without the solvation electrostatics contribution. An ensemble of beta beta alpha conformations was found at and near the global minimum of the energy function with the REBEL electrostatic solvation term. Much poorer correspondence to the native solution structure was found in the "control" simulations with a traditional method to account for solvation via a distance-dependent dielectric constant. Each simulation took less than 40 h (21 h without electrostatic solvation calculation) on a single Alpha 677 MHz CPU and involved more than 40,000 solvation energy evaluations. This work demonstrates for the first time that such a simulation can be performed in a realistic time frame. The proposed procedure may eliminate the energy evaluation accuracy bottleneck in folding simulations.

Algorithms↗
PubMed2001

Effects of the incorporation of CHAPS into SDS micelles on neuropeptide-micelle binding: separation of the role of electrostatic interactions from hydrophobic interactions.

It is well known that neuropeptides interact with lipid vesicles in a manner similar to biological membranes, with electrostatic interactions between the two providing a mechanism for concentrating the peptide at the vesicle's surface, followed by hydrophobic interactions between the peptide and the core of the vesicle that induce and stabilize secondary structure motifs. In an effort to understand these interactions to a greater extent, our group has developed a series of anionic micelles (SDS) containing various concentrations of the bile salt CHAPS, which is used as a model for cholesterol. The incorporation of CHAPS into the hydrophobic core of these micelles should alter the degree to which the neuropeptide can insert itself, affecting structure. These interactions were investigated using two-dimensional NMR, pulse-field gradient (PFG) NMR, and molecular modeling experiments. The results of this study clearly indicate that electrostatic and hydrophobic interactions between the micelle and neuropeptide are completely independent of one another. Increasing the concentration of CHAPS to 15 mM in the micelles blocks the insertion of the hydrophobic side chains of the neuropeptide into the hydrophobic core of the micelles. The electrostatic interactions as determined by diffusion measurements are not affected by the presence of increasing CHAPS concentration. Our observations are consistent with the predictions of Seelig (A. Seelig and J. Seelig, "Interaction of Drugs and Peptides with the Lipid Membrane," in Structure and Function of 7TM Receptors, T. W. Schwartz, S. A. Hjorth, and T. S. Kastrup, Eds., Munksgaard: Location, 1996).

Cholic Acids↗
PubMed2002

Close-range electrostatic interactions in proteins.

Two types of noncovalent bonding interactions are present in protein structures, specific and nonspecific. Nonspecific interactions are mostly hydrophobic and van der Waals. Specific interactions are largely electrostatic. While the hydrophobic effect is the major driving force in protein folding, electrostatic interactions are important in protein folding, stability, flexibility, and function. Here we review the role of close-range electrostatic interactions (salt bridges) and their networks in proteins. Salt bridges are formed by spatially proximal pairs of oppositely charged residues in native protein structures. Often salt-bridging residues are also close in the protein sequence and fall in the same secondary structural element, building block, autonomous folding unit, domain, or subunit, consistent with the hierarchical model for protein folding. Recent evidence also suggests that charged and polar residues in largely hydrophobic interfaces may act as hot spots for binding. Salt bridges are rarely found across protein parts which are joined by flexible hinges, a fact suggesting that salt bridges constrain flexibility and motion. While conventional chemical intuition expects that salt bridges contribute favorably to protein stability, recent computational and experimental evidence shows that salt bridges can be stabilizing or destabilizing. Due to systemic protein flexibility, reflected in small-scale side-chain and backbone atom motions, salt bridges and their stabilities fluctuate in proteins. At the same time, genome-wide, amino acid sequence composition, structural, and thermodynamic comparisons of thermophilic and mesophilic proteins indicate that specific interactions, such as salt bridges, may contribute significantly towards the thermophilic-mesophilic protein stability differential.

Amino Acids↗
PubMed1991

Structural and genetic analysis of electrostatic and other interactions in bacteriophage T4 lysozyme.

The lysozyme from bacteriophage T4 is being used as a model system to determine the roles of individual amino acids in the folding and stability of a typical globular protein. Such studies can provide quantitative information on the contributions made by different types of interactions including hydrogen bonds, hydrophobic interactions, salt bridges and disulphide bridges. To determine the contribution of long-range electrostatic interactions a combination of charge-change mutations was used to reduce the overall formal charge on T4 lysozyme at neutral pH from +9 to +1 units. Such changes in charge were found to have little effect on the stability of the molecule. Salt bridges engineered on the surface of the protein also were found to contribute little to stability. In contrast, the introduction of acidic groups designed to interact with the partial positive charges at the N-termini of alpha-helices consistently increased the stability of the protein. It is argued that this difference between electrostatic salt-bridge interactions and electrostatic 'helix-dipole' interactions lies in the entropic cost of bringing together the interacting partners. In an attempt to simplify the folding problem, and also to further investigate the helix propensity of different amino acids, a series of alanines was introduced within an alpha-helix of T4 lysozyme. The resultant protein not only folds normally but is also more stable than the wild-type enzyme, adding further support to recent evidence that alanine is a helix-favouring amino acid.

Electricity↗
PubMed2003

Study of electrostatic potential surface distribution of wild-type plastocyanin Synechocystis solution structure determined by homonuclear NMR.

Plastocyanin is a small (approximately 10 kDa), type I blue copper protein that works as an electron donor to photosystem I from cytochrome f in both chloroplast systems and in some strains of cyanobacteria. Comparative studies of the kinetic mechanisms of plastocyanins in different organisms show that the electron transfer from photosystem I happens by simple collision in cyanobacteria but through a intermediate transition complex in green algae and superior plants. Previous work has proved that this effect cannot be explained by structural variations across the different plastocyanins but it can be explained by differences in the electrostatic potential distribution at the protein surface. In that case, minor conformational errors at the amino acid side chain level may imply an important effect in the electrostatic potential distribution calculation. In this work we present a high resolution study of side chain conformation by homonuclear NMR for the reduced wild-type plastocyanin Synechocystis using intensity ratios for 2D-NOESY and 2D-H,H-TOCSY cross peaks at different mixing times. We also present the corresponding comparison with different plastocyanin structures and the effect in the electrostatic potential distribution at the protein surface. We discuss the importance of indirect J-coupling information from TOCSY-type experiments as complement for intraresidue distances derived from NOESY experiments in the determination of side chain orientation and stereo-specific assignments.

Cyanobacteria↗
PubMed2004

Ribosome motions modulate electrostatic properties.

The electrostatic properties of the 70S ribosome of Thermus thermophilus were studied qualitatively by solving the Poisson-Boltzmann (PB) equation in aqueous solution and with physiological ionic strength. The electrostatic potential was calculated for conformations of the ribosome derived by recent normal mode analysis (Tama, F., et al. Proc Natl Acad Sci USA 2003 100, 9319-9323) of the ratchet-like reorganization that occurs during translocation (Frank, J.; Agrawal, R. K. Nature 2000 406, 318-322). To solve the PB equation, effective parameters (charges and radii), applicable to a highly charged backbone model of the ribosome, were developed. Regions of positive potential were found at the binding site of the elongation factors G and Tu, as well as where the release factors bind. Large positive potential areas are especially pronounced around the L11 and L6 proteins. The region around the L1 protein is also positively charged, supporting the idea that L1 may interact with the E-site tRNA during its release from the ribosome after translocation. Functional rearrangement of the ribosome leads to electrostatic changes which may help the translocation of the tRNAs during the elongation stage.

Binding Sites↗