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PubMed1997

Optimization of the electrostatic interactions between ionized groups and peptide dipoles in proteins.

The three-dimensional optimization of the electrostatic interactions between the charged amino acid residues and the peptide partial charges was studied by Monte-Carlo simulations on a set of 127 nonhomologous protein structures with known atomic coordinates. It was shown that this type of interaction is very well optimized for all proteins in the data set, which suggests that they are a valuable driving force, at least for the native side-chain conformations. Similar to the optimization of the charge-charge interactions (Spassov VZ, Karshikoff AD, Ladenstein R, 1995, Protein Sci 4:1516-1527), the optimization effect was found more pronounced for enzymes than for proteins without enzymatic function. The asymmetry in the interactions of acidic and basic groups with the peptide dipoles was analyzed and a hypothesis was proposed that the properties of peptide dipoles are a factor contributing to the natural selection of the basic amino acids in the chemical composition of proteins.

Amino Acids↗
PubMed1997

Structural analysis of three His32 mutants of DsbA: support for an electrostatic role of His32 in DsbA stability.

DsbA, a 21-kDa protein from Escherichia coli, is a potent oxidizing disulfide catalyst required for disulfide bond formation in secreted proteins. The active site of DsbA is similar to that of mammalian protein disulfide isomerases, and includes a reversible disulfide bond formed from cysteines separated by two residues (Cys30-Pro31-His32-Cys33). Unlike most protein disulfides, the active-site disulfide of DsbA is highly reactive and the oxidized form of DsbA is much less stable than the reduced form at physiological pH. His32, one of the two residues between the active-site cysteines, is critical to the oxidizing power of DsbA and to the relative instability of the protein in the oxidized form. Mutation of this single residue to tyrosine, serine, or leucine results in a significant increase in stability (of approximately 5-7 kcal/mol) of the oxidized His32 variants relative to the oxidized wild-type protein. Despite the dramatic changes in stability, the structures of all three oxidized DsbA His32 variants are very similar to the wild-type oxidized structure, including conservation of solvent atoms near the active-site residue, Cys30. These results show that the His32 residue does not exert a conformational effect on the structure of DsbA. The destabilizing effect of His32 on oxidized DsbA is therefore most likely electrostatic in nature.

Binding Sites↗
PubMed1998

Trifluoroethanol effects on helix propensity and electrostatic interactions in the helical peptide from ribonuclease T1.

Trifluoroethanol (TFE) is often used to increase the helicity of peptides to make them usable as models of helices in proteins. We have measured helix propensities for all 20 amino acids in water and two concentrations of trifluoroethanol, 15 and 40% (v/v) using, as a model system, a peptide derived from the sequence of the alpha-helix of ribonuclease T1. There are three main conclusions from our studies. (1) TFE alters electrostatic interactions in the ribonuclease T1 helical peptide such that the dependence of the helical content on pH is lost in 40% TFE. (2) Helix propensities measured in 15% TFE correlate well with propensities measured in water, however, the correlation with propensities measured in 40% TFE is significantly worse. (3) Propensities measured in alanine-based peptides and the ribonuclease T1 peptide in TFE show very poor agreement, revealing that TFE greatly increases the effect of sequence context.

Amino Acid Sequence↗
PubMed1998

Electrostatic coupling to pH-titrating sites as a source of cooperativity in protein-ligand binding.

This paper describes an alternative mechanism for the cooperative binding of charged ligands to proteins. The ligand-binding sites are electrostatically coupled to protein side chains that can undergo protonation and deprotonation. The binding of one ligand alters the protein's protonation equilibrium in a manner that makes the the binding of the second ligand more favorable. This mechanism requires no conformational change to produce a cooperative effect, although it is not exclusive of conformational change. We present a theoretical description of the mechanism, and calculations on three kinds of systems: A model system containing one protonation site and two ligand-binding sites; a model system containing two protonation sites and two ligand-binding sites; and calbindin D9k, which contains two Ca2+-binding sites and 30 protonation sites. For the one-protonation-site model, it is shown that the influence of the protonation site can only be cooperative. The competition of this effect with the anticooperative effect of ligand-ligand repulsion is studied in detail. For the two-protonation site model, the effect can be either cooperative or, in special cases, anticooperative. For calbindin D9k, the calculations predict that six protonation sites in or near the ligand-binding sites make a cooperative contribution that approximately cancels the anticooperative effect of Ca2+-Ca2+ repulsion, accounting for more than half of the total cooperative effect that is needed to overcome repulsion and produce the net cooperativity observed experimentally. We argue that cooperative mechanisms of the kind described here are likely when there is more than one ligand-binding site in a protein domain.

Binding Sites↗
PubMed2002

A critical analysis of continuum electrostatics: the screened Coulomb potential--implicit solvent model and the study of the alanine dipeptide and discrimination of misfolded structures of proteins.

An analysis of the screened Coulomb potential--implicit solvent model (SCP--ISM) is presented showing that general equations for both the electrostatic and solvation free energy can be derived in a continuum approach, using statistical averaging of the polarization field created by the solvent around the molecule. The derivation clearly shows how the concept of boundary, usually found in macroscopic approaches, is eliminated when the continuum model is obtained from a microscopic treatment using appropriate averaging techniques. The model is used to study the alanine dipeptide in aqueous solution, as well as the discrimination of native protein structures from misfolded conformations. For the alanine dipeptide the free energy surface in the phi--psi space is calculated and compared with recently reported results of a detailed molecular dynamics simulation using an explicit representation of the solvent, and with other available data. The study showed that the results obtained using the SCP--ISM are comparable to those of the explicit water calculation and compares favorably to the FDPB approach. Both transition states and energy minima show a high correlation (r > 0.98) with the results obtained in the explicit water analysis. The study of the misfolded structures of proteins comprised the analysis of three standard decoy sets, namely, the EMBL, Park and Levitt, and Baker's CASP3 sets. In all cases the SCP--ISM discriminated well the native structures of the proteins, and the best-predicted structures were always near-native (cRMSD approximately 2 A).

Alanine↗
PubMed2002

Docking unbound proteins using shape complementarity, desolvation, and electrostatics.

A comprehensive docking study was performed on 27 distinct protein-protein complexes. For 13 test systems, docking was performed with the unbound X-ray structures of both the receptor and the ligand. For the remaining systems, the unbound X-ray structure of only molecule was available; therefore the bound structure for the other molecule was used. Our method optimizes desolvation, shape complementarity, and electrostatics using a Fast Fourier Transform algorithm. A global search in the rotational and translational space without any knowledge of the binding sites was performed for all proteins except nine antibodies recognizing antigens. For these antibodies, we docked their well-characterized binding site-the complementarity-determining region defined without information of the antigen-to the entire surface of the antigen. For 24 systems, we were able to find near-native ligand orientations (interface C(alpha) root mean square deviation less than 2.5 A from the crystal complex) among the top 2,000 choices. For three systems, our algorithm could identify the correct complex structure unambiguously. For 13 other complexes, we either ranked a near-native structure in the top 20 or obtained 20 or more near-native structures in the top 2,000 or both. The key feature of our algorithm is the use of target functions that are highly tolerant to conformational changes upon binding. If combined with a post-processing method, our algorithm may provide a general solution to the unbound docking problem. Our program, called ZDOCK, is freely available to academic users (http://zlab.bu.edu/~rong/dock/).

Algorithms↗
PubMed2001

Focusing of the electrostatic potential at EF-hands of calbindin D(9k): titration of acidic residues.

Biological functions for a large class of calmodulin-related proteins, such as target protein activation and Ca(2+) buffering, are based on fine-tuned binding and release of Ca(2+) ions by pairs of coupled EF-hand metal binding sites. These are abundantly filled with acidic residues of so far unknown ionization characteristics, but assumed to be essential for protein function in their ionized forms. Here we describe the measurement and modeling of pK(a) values for all aspartic and glutamic acid residues in apo calbindin D(9k), a representative of calmodulin-related proteins. We point out that while all the acidic residues are ionized predominantly at neutral pH, the onset of proton uptake by Ca(2+) ligands with high pK(a) under these conditions may have functional implications. We also show that the negative electrostatic potential is focused at the bidental Ca(2+) ligand of each site, and that the potential is significantly more negative at the N-terminal binding site.

Animals↗
PubMed2006

Electrostatic interactions of peptides flanking the tyrosine kinase domain in the epidermal growth factor receptor provides a model for intracellular dimerization and autophosphorylation.

The mechanism by which ligand-activated EGFR induces autophosphorylation via dimerization is not fully understood. Structural studies have revealed an extracellular loop mediated receptor dimerization. We have previously presented experimental data showing the involvement of a positive 13 amino acid peptide (R645-R657; P13+) from the intracellular juxtamembrane domain (JM) of EGFR important for intracellular dimerization and autophosphorylation. A model was presented that suggest that P13+ interacts with a negative peptide (D979-E991; P13-) positioned distal to the tyrosine kinase domain in the opposite EGFR monomer. The present work shows additional data strengthening this model. In fact, by analyzing protein sequences of 21 annotated ErbB proteins from 9 vertebrate genomes, we reveal the high conservation of peptides P13+ and P13- with regard to their sequence as well as their position relative to the tyrosine kinase (TK) domain. Moreover in silico structure modeling of these ErbB intracellular domains supports a general electrostatic P13+/P13- interaction, implying that the C-terminal of one receptor monomer is facing the TK domain of the other monomer in the receptor dimer and vice versa. This model provides new insights into the molecular mechanism of ErbB receptor activation and suggests a new strategy to pharmacologically interfering with ErbB receptor activity.

Animals↗
PubMed2006

Molecular mechanisms of pH-driven conformational transitions of proteins: insights from continuum electrostatics calculations of acid unfolding.

The acid unfolding of staphylococcal nuclease (SNase) is very cooperative (Whitten and García-Moreno, Biochemistry 2000;39:14292-14304). As many as seven hydrogen ions (H+) are bound preferentially by the acid-unfolded state relative to the native (N) state in the pH range 3.2-3.9. To investigate the mechanism of acid unfolding, structure-based pKa calculations were performed with a variety of continuum electrostatic methods. The calculations reproduced successfully the H+ binding properties of the N state between pH 5 and 9, but they systematically overestimated the number of H+ bound upon acid unfolding. The calculated pKa values of all carboxylic residues in the N state were more depressed than they should be. The discrepancy between the observed and the calculated H+ uptake upon acid unfolding was not improved by using high protein dielectric constants, structures relaxed with molecular dynamics, or other empirical modifications implemented previously by others to maximize agreement between measured and calculated pKa values. This suggests an important role for conformational fluctuations of the backbone as important determinants of pKa values of carboxylic groups. Because no global or subglobal conformational changes have been observed previously for SNase under acidic conditions above the acid-unfolding region, these fluctuations must be local. The acid unfolding of SNase does not seem to involve the disruption of the N state by accruement of intramolecular repulsive interactions, nor the protonation of key ion paired carboxylic residues. It is more consistent with modest contributions from many H+ binding groups, with an important role for local conformational fluctuations in the coupling between H+ binding and the global structural transition.

Acids↗
PubMed2001

Enhanced efficiency of electrostatically charged insecticide aerosols.

The bioefficacy of a standard domestic aerosol insecticide has been compared with that of a similar spray in which the droplets were electrostatically charged. The aerosol was charged without the need for an external power supply, by enhancing natural charge separation processes that occur during atomisation. The charge-to-mass ratio achieved was 1.1 x 10(-4) C kg-1, compared with 2.2 x 10(-5) C kg-1 for the standard aerosol. Efficiency was assessed for insects in free flight. A direct space-spray application method was used to study the bioefficacy of these aerosols on houseflies, Musca domestica, and an indirect space-spray method on houseflies and mosquitoes, Culex quinquefasciatus. Two levels of concentration of active ingredients were compared. At low concentrations of 1.57 g kg-1 of bioallethrin and 0.29 g kg-1 of bioresmethrin, the charged aerosol achieved a significant reduction in KDT50 (time at which 50% of the flies were knocked down), compared with the standard aerosol. In the direct spray application to houseflies, the KDT50 was reduced by 50%, while in the indirect spray the KDT50 was reduced by 40%. In the indirect spray of mosquitoes, the KDT50 was reduced by 22%. With higher active ingredient concentrations of 2.09 g kg-1 for bioallethrin and 0.39 g kg-1 for bioresmethrin, the charged aerosol also demonstrated faster knockdown than the standard, but the improvement was less marked. In the direct spray application to houseflies, the KDT50 was reduced by 21% compared with the standard aerosol, while in the indirect spray the KDT50 was reduced by 16%. In the indirect spray of mosquitoes, the KDT50 was reduced by 24%. The percentage mortality after 24 h was also increased with the charged aerosol. Charge carried by the droplets results in increased interception of the insecticide, as the droplets are attracted to the insects in flight and space charge effects within the aerosol could cause improved dispersion in the test chamber.

Aerosols↗
PubMed2002

Effect of surface material on electrostatic charging of houseflies (Musca domestica L).

Houseflies (Musca domestica L) accumulated electrostatic charges when walking over clean, uncharged dielectric surfaces. The charges elicited on a walking housefly by a range of materials were quantified, allowing a triboelectric series to be determined relative to M domestica. This ranged from surfaces that charged individuals positively, e.g. Correx (corrugated polypropylene) [.1 (+/- 4.2)pC], to those that applied a negative charge, e.g. clear cast acrylic [-14.9 (+/- 2.9)pC]. Maximum positive and negative charges accumulated by individual M domestica were +73 and -27 pC. Replicate measurements on the same fly and surface showed little variation. Variation between individuals was not related to sex and was not consistent between surfaces. Different materials charged M domestica significantly differently and individual flies had significantly different charging properties. Variation in temperature between 21.3 degrees C and 24.7 degrees C and humidity between 24% and 41% RH significantly affected charge accumulated by M domestica on some surfaces, although further experimentation is needed to confirm this. The implications of this work are discussed in relation to insect trap design and pollination biology.

Acetals↗
PubMed1984

Potential derived point charge model study of electrostatic interaction energies in some complexes of water with uracil, thymine, and cytosine.

Potential derived (PD) point charges and segmental multipole moments are calculated for water, uracil, thymine, and cytosine using STO-3G quality wave functions. The PD point charges are used to estimate the electrostatic interaction energies for a series of complexes of water with these nucleic acid bases. It is shown here that the results obtained using simple PD charge model is very similar to those obtained from more elaborate segmental multipole moment analysis.

Algorithms↗
PubMed1993

Redox potential and electrostatic effects in competitive inhibition of dual-path electron transfer reactions of spinach plastocyanin.

Redox inactive ions with high positive charges lower the rate constant for oxidation of several plant plastocyanins (PC) by small positively charged inorganic reaction partners. The rate constant decrease is commonly attributed to competitive inhibition where the redox inactive ions are bound to the negatively charged remote electron transfer (ET) site of PC and block this site sterically. We have investigated the effects of the inhibitor [NH3)5Co(NH2)Co(NH3)5]5+ on the ET reactions of spinach PC with [Co(phen)3]3+ (phen = 1,10-phenanthroline) and the electrically neutral analogue [Co(phen-SO3)3] (phen-SO3 = 5-sulfonato-1,10-phenanthroline) at the ionic strengths mu = 0.1 M and 0.03 M. Inhibition of the [Co(phen)3]3+ reactions is notably smaller for PC(II) reduction than for PC(I) oxidation. This is indicative of a redox potential increase of PC(II)/PC(I) on inhibitor attachment. The effect amounts to 16 mV at mu = 0.1 M and 31 mV at mu = 0.03 M. These data, and analysis in terms of ET theory show that inhibition cannot be caused solely by steric blocking. Driving force and interreactant electrostatic work terms are equally important. The PC(I)/[Co(phen-SO3)3] reaction exhibits a more entangled pattern. The rate constant first increases slightly with increasing inhibitor concentration, then drops, and approaches a constant value not far from the original value. This pattern is in line with association between the negatively charged -SO3- groups of the Co(III) complex and the inhibitor, and ET of the associate at both ET sites of PC.

Binding, Competitive↗
PubMed1999

Electrostatically mediated interactions between cationic lipid-DNA particles and an anionic surface.

In an effort to model the interaction of lipid-based DNA delivery systems with anionic surfaces, such as a cell membrane, we have utilized microelectrophoresis to characterize how electrokinetic measurements can provide information on surface charge and binding characteristics. We have established that cationic lipids, specifically N-N-dioleoyl-N,N-dimethylammonium chloride (DODAC), incorporated into liposomes prepared with 1, 2-dioleoyl-i-glycero-3-phosphoethanolamine (DOPE) or 1, 2-dioleoyl-sn-glycero-3-phosphocholine (DOPC) at 50 mol%, change the inherent electrophoretic mobility of anionic latex polystyrene beads. Self-assembling lipid-DNA particles (LDPs), prepared at various cationic lipid to negative DNA phosphate charge ratios, effected no changes in bead mobility when the LDP charge ratio (+/-) was equal to or less than 1. Increasing the LDP concentration in a solution of 0.1% (w/v) anionic beads resulted in a charge reversal effect when a net charge of LDP to total bead charge ratio (+/-) of 1:1 was observed. LDP formulations, utilizing either DOPE or DOPC, showed similar titration profiles with a charge reversal observed at a 1:1 net LDP to bead charge ratio (+/-). It was confirmed through centrifugation studies that the DNA in the LDP was associated with the anionic latex beads through electrostatic interactions. LDP binding, rather than the binding of dissociated cationic lipids, resulted in the observed electrophoretic mobility changes of the anionic latex beads.

Anions↗
PubMed1998

Aggrecan immobilization onto polystyrene plates through electrostatic interactions with spermine.

A new procedure for the immobilization of proteoglycans and the core protein thereof via their carbohydrate chains onto enzyme-linked immunosorbent assay (ELISA) plate wells is presented. The aggrecan was immobilized via electrostatic interactions with spermine coupled to glutaraldehyde via Schiff's base, the latter being directly anchored onto ELISA wells. The amounts of aggrecan bound by this procedure measured immunochemically were 10-fold greater than those adsorbed by direct coating. The interaction of aggrecan and spermine may be inhibited by very small amounts of sulfated glycosaminoglycans or proteoglycans in a competitive manner, and therefore the system may be used for their quantitation. Bound aggrecan could react with link protein and therefore the system may be used for studying interactions of cartilage macromolecules. The method may also be used for direct quantitation of proteoglycans since the amounts adsorbed, in a given range of concentrations, are directly proportional to the amounts in solution.

Aggrecans↗
PubMed1994

Electrostatic activation of rat phenylalanine hydroxylase.

The conversion of phenylalanine to tyrosine is accelerated approximately five fold by phosphorylation of the enzyme which catalyzes this step, phenylalanine hydroxylase. To gain a clearer understanding of the mechanism of this activation, we have applied site-directed mutagenesis to specifically modify a clone of the hydroxylase at the phosphorylation site, the serine at position 16. We converted this serine residue to alanine and to glutamic acid. The wild-type and mutant proteins were purified and the activation states of the enzymes were examined with respect to the single phosphorylation site at position 16. Substitution of Ser16 with a negatively charged Glu residue resulted in activation of the enzyme, whereas substitution with an uncharged Ala residue did not. These results indicate that activation of the native enzyme by phosphorylation is due to the introduction of a negative charge, and suggest involvement of electrostatic interactions.

Alanine↗
PubMed1995

Increased activity of porcine pancreatic phospholipase A2 by designed long-range electrostatic stabilisation of the transition state.

Stabilisation of the catalytic transition state by long-range charge interactions has been tested with mutagenesis for porcine pancreatic phospholipase A2. Electrostatics calculations were used to determine locations which would interact preferentially with one part of the dipolar charge separation that is believed to develop in the transition state. Experiment shows increased enzyme activity relative to wild-type recombinant enzyme for mutants N97D and N101D, consistent with the design.

Animals↗
PubMed1998

Role of carboxyl residues surrounding heme of human cytochrome b5 in the electrostatic interaction with NADH-cytochrome b5 reductase.

To identify the cytochrome b5 residues responsible for the electrostatic interaction with NADH-cytochrome b5 reductase (b5R), we prepared and characterized the cytochrome b5 mutants in which Glu41, Glu42, Glu63, Asp70, and Glu73 were replaced by Ala, utilizing site-directed mutagenesis and the expression system for cytochrome b5 in Escherichia coli. Apparent Km values of the wild type b5R for Glu42Ala cytochrome b5 and Asp70Ala cytochrome b5 were approximately three-fold and six-fold higher than that for the wild type cytochrome b5, respectively, while the kcat values for those mutants were not remarkably affected. In contrast, Glu41Ala, Glu63Ala, and Glu73Ala cytochrome b5 showed almost the same kinetic properties as the wild type cytochrome b5. Furthermore, kinetic studies on combinations of the cytochrome b5 and b5R mutants suggested the interaction between Glu42 and Asp70 of cytochrome b5 and Lys125 and Lys41 of b5R, respectively, in the reaction.

Amino Acid Substitution↗