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At least 505 records · Page 28Linked to original sources
PubMed1995

The myristoyl-electrostatic switch: a modulator of reversible protein-membrane interactions.

Hydrophobic insertion of the acyl chain into the bilayer is necessary but not sufficient for the membrane binding of a myristoylated protein. The myristoylated alanine-rich C kinase substrate (MARCKS), Src, ADP-ribosylation factor and human immunodeficiency virus-1 matrix proteins also contain a cluster of basic residues that bind to acidic phospholipids; the hydrophobic and electrostatic interactions act together to anchor the protein to a membrane. For MARCKS, and perhaps other proteins, phosphorylation of serines within its basic cluster reduces the electrostatic attraction, producing translocation of the protein from the membrane to the cytosol by a simple 'electrostatic switch' mechanism.

Cell Membrane↗
PubMed2001

Relation between the molecular electrostatic potential and activity of some FF-MAS related sterol compounds.

Follicular Fluid-Meiosis Activating Sterol (FF-MAS) is a compound important for maturation of gametes in mammals. Therefore, it may serve as a lead compound for a novel method of contraception. We studied the Molecular Electrostatic Potential of a series of active and inactive analogues of FF-MAS. We find that double bond configurations required for activity result in a local negative electrostatic potential which is larger as well as more dense compared to those of inactive molecules. We therefore hypothesize that the interaction energy of the double bond system of the MAS compounds with its receptor substantially contributes to the overall interaction energy. This notion is supported by interaction studies of the electrostatic potential originating from the double bonds in crystal structures of cholesterol and four MAS-derived Delta(8,14) structures synthesized and crystallized by us. In addition, we were able to derive a pharmacophore model that relates the local average ESP and its distance to the 3beta-OH oxygen atom to the activity of the molecules.

Animals↗
PubMed1997

Local electrostatic potentials in pyridoxal phosphate labelled horse heart cytochrome c.

The present work shows the application of an optical label pyridoxal phosphate (PLP) for the experimental determination of local electrostatic potentials in singly substituted cytochromes c modified by pyridoxal phosphate at Lys 79 (PLP-Lys-79-cyt.c) or at Lys 86 (PLP-Lys-86-cyt.c). PLP has also been used to calculate the pKa values of all ionizable groups and the electrostatic potentials in the modified proteins and to analyse their properties. The experimental pKa values for the pyridine nitrogen and phenolic hydroxyl of the bound label were obtained from pH-dependent absorbance and fluorescence measurements, as follows: in PLP-Lys-79-cyt.c for pyridine nitrogen 4.5 (absorbance) and 5.1 (fluorescence), for phenolic hydroxyl 8.6 (absorbance) and 8.3 (fluorescence); in PLP-Lys-86-cyt.c for pyridine nitrogen 4.7 (absorbance) and 5.8 (fluorescence), for phenolic hydroxyl 8.3 (absorbance) and 8.5 (fluorescence). The differences between absorbance and fluorescence data are related to differences in the behaviour of the bound label in the ground and excited electronic states and to intermolecular charge-charge interactions. Molecular modelling was used to generate the atomic co-ordinates of the PLP-modified horse heart cytochrome c necessary for the theoretical calculations of the pKa values and electrostatic potentials.

Animals↗
PubMed2003

Multi-way PLS modeling of structure-activity data by incorporating electrostatic and lipophilic potentials on molecular surface.

We devised and elaborated a surface-based three-dimensional-quantitative structure-activity relationship (3D-QSAR) method, which had been proposed in the previous study. This approach can be applied to more general case where both the electrostatic and lipophilic potentials on molecular surface simultaneously change. The 3D coordinates of all sampling points on molecular surface are projected into a 2D map by Kohonen neural network (KNN). Each node in the map is coded by the associated molecular electrostatic potential (MEP) or molecular lipophilic potential (MLP) values. The electrostatic and lipophilic KNN maps are generated for each compound and the four-way array is constructed by collecting two KNN maps of all samples. The correlation between four-way array and biological activity is examined by four-way partial least-squares (PLS). For validation, the structure-activity data of estrogen receptor antagonists was investigated. The four-way PLS model gave the high statistics at calibration and validation stages. The coefficients of the four-way PLS model back-projected on molecular surface had a reasonable 3D distribution and it was nicely consistent with active site of the estrogen receptor which was recently made clear by X-ray crystallography.

Journal Article↗
PubMed1992

Mechanistic studies of electrostatic potentials on antigen--antibody complexes for bioanalyses.

A concept involving the use of antibodies conjugated with reporter molecules for the direct sensing on the subtle changes in the local electrostatic environment of antigen-antibody complexes due to the antigen binding was proposed and demonstrated. The studies including the effect of solution conditions on the extent and magnitude of the electrostatic potentials around the antigen-antibody complex and the quantitative dependence of the distance between the reporter molecule and the antigen-antibody binding site on the effectiveness of the reporter molecule for sensing the antigen-antibody binding event are presented and discussed. Basic understanding of induced changes in the electrostatic potentials on the antigen-antibody complex is essential for implementing the proposed direct sensing mechanism.

Amino Acid Sequence↗
PubMed2005

Electrostatic contributions to protein retention in ion-exchange chromatography. 2. Proteins with various degrees of structural differences.

The relation of protein structure to retention provides a framework within which to investigate chromatographic adsorption mechanisms. Protein sets with varying degrees of structural differences were studied to relate variations in protein properties to retention behavior. To explore molecular contributions to protein adsorption in ion-exchange chromatography, protein-adsorbent electrostatic interactions were modeled using a continuum approach. The calculations qualitatively capture the chromatographic differentiation of closely related subtilisin variants. Descriptions of the electrostatic interactions of FGF-1 vs FGF-2 with cation exchangers were obtained, and aid in rationalizing differences in experimental retention trends across a set of adsorbents based on different adsorption mechanisms linked to the adsorbent structure. Comparative calculations for proteins with differences in local or overall arginine-lysine composition, including subtilisin variants G166R/G166K and lysozyme/cytochrome c, suggest that continuum electrostatics is not adequate to capture the full quantitative characteristics of the chromatographic retention of proteins. To allow more accurate description of retention, additional molecular interactions, specifically hydration effects, must be incorporated in the model.

Arginine↗
PubMed2007

Tailoring elution of tetraalkylammonium ions. Ideal electrostatic selectivity elution order on a polymeric ion exchanger.

Although ion exchange is often depicted as a process driven by electrostatic forces, ionic solvation or hydrophobic forces contribute greatly to ion exchange selectivity and is often the dominant factor. On a variety of commercial anion exchange columns, monovalent ClO4- elutes after doubly charged SO42- and even triply charged PO43-. For identically charged alkali metal ions, electrostatic charge densities based on crystal radii would suggest Li+ to be the most strongly retained on a cation exchanger. In practice, it is typically the least strongly held cation on most cation exchangers, because of its very high hydration energy and with most eluents its capacity factor approaches zero. Even when the ion is very poorly solvated, as with tetraalkylammonium (NR4+) cations, there has never been a report on a polymeric ion exchanger of an ideal electrostatic selectivity order where NR4+ cations elute in their increasing charge density order: R = n-butyl first, followed by n-propyl, ethyl, and last, methyl. We show that this selectivity order is easily achieved on recently described methracrylate-based monolithic capillary cation exchange columns (Ueki, Y.; Umemura, T.; Li, J. X.; Odake, T; Tsunoda, K. Anal. Chem. 2004, 76, 7007-7012) with minor amounts of hydroorganic modifiers. Indeed, under such conditions, Li+ (and other alkali cations) elutes after NMe4+.

Journal Article↗
PubMed2002

Electrostatic assembly of nanoparticles and biomacromolecules.

The controlled assembly of nanoparticles in thin film form on solid supports, both as monolayers and as superlattice structures, is a problem of considerable topical interest. Among the many interactions used to program the assembly of nanoparticles, electrostatic forces are particularly interesting for many reasons. This Account deals with assembling surface-modified nanoparticles in thin film form using electrostatic interactions at the air-water interface and in thermally evaporated lipid films. The generality of the electrostatic assembly protocol is demonstrated in the immobilization of DNA and proteins in lipid films.

Air↗
PubMed1995

[Lys(-2)-Arg(-1)]endothelin-1 solution structure by two-dimensional 1H-NMR: possible involvement of electrostatic interactions in native disulfide bridge formation and in biological activity decrease.

Addition of the Lys(-2)-Arg(-1) dipeptide, present in the precursor protein, to the N-terminus of endothelin-1 (ET-1), to form a 23-residue peptide (KR-ET-1) has been shown to greatly improve formation of native disulfide bridges and to dramatically decrease biological activity. Conformational analysis was carried out on this peptide. During protonation of the carboxyl groups, CD spectra showed a decrease in the helical contribution, and NMR spectra displayed strong chemical shift modifications, suggesting the importance of electrostatic interactions in the KR-ET-1 conformation. CD spectra and two-dimensional NMR experiments were performed to investigate the KR-ET-1 three-dimensional structure in water in the carboxylic acid and carboxylate states. Distance and angle constraints were used as input for distance geometry calculations. The KR-ET-1 carboxylic acid conformation was found to be very similar to ET-1, with a helix spanning residues 9-15 and an unconstrained C-terminal part. In contrast, in the carboxylate state, large changes in Arg(-1) and Phe14 chemical shifts and long-range NOEs were consistent with a conformation characterized by a helix extension to Leu17 and a stabilized C-terminal section folded back toward the N-terminus. In addition, thanks to NOEs with Cys11 and Phe14, the Arg(-1) side chain appeared well-defined. Simulated annealing and molecular dynamics calculations, supported an Arg(-1)-Glu10 salt bridge and an electrostatic network involving the charged groups of Trp21, Asp18, and Lys(-2). Moreover, stabilization of the KR-ET-1 C-terminal part is probably reinforced by hydrophobic interactions involving the Val12, Tyr13, Phe14, Leu17, Ile19, Ile20, and Trp21 side chains. In vitro, native disulfide bond formation improvement observed for KR-ET-1 could be ascribed to electrostatic interactions and more specifically to the Arg(-1)-Glu10 salt bridge. In vivo, similar interactions could play an important role in the native folding of the ET-1 precursor protein. On the other hand, modification in the environment and a reduced mobility of the KR-ET-1 Trp21 key residue, when compared to ET-1, could explain, at least in part, the strong decrease in biological activity.

Acetates↗
PubMed2000

Involvement of electrostatic interactions in the mechanism of peptide folding induced by sodium dodecyl sulfate binding.

Sodium dodecyl sulfate (SDS) has consistently been shown to induce secondary structure, particularly alpha-helices, in polypeptides, and is commonly used to model membrane and other hydrophobic environments. However, the precise mechanism by which SDS induces these conformational changes remains unclear. To examine the role of electrostatic interactions in this mechanism, we have designed two hydrophilic, charged amphipathic alpha-helical peptides, one basic (QAPAYKKAAKKLAES) and the other acidic (QAPAYEEAAEELAKS), and their structures were studied by CD and NMR. The design of the peptides is based on the sequence of the segment of residues 56-70 of human platelet factor 4 [PF4(56-70), QAPLYKKIIKKLLES]. Both peptides were unstructured in water, and in the presence of neutral, zwitterionic, or cationic detergents. However, in SDS at neutral pH, the basic peptide folded into an alpha-helix. By contrast, the pH needed to be lowered to 1.8 before alpha-helix formation was observed for the acidic peptide. Strong, attractive electrostatic interactions, between the anionic groups of SDS and the cationic groups of the lysines, appeared to be necessary to initiate the folding of the basic peptide. NMR analysis showed that the basic peptide was fully embedded in SDS-peptide micelles, and that its three-dimensional alpha-helical structure could be superimposed on that of the native structure of PF4(56-70). These results enabled us to propose a working model of the basic peptide-SDS complex, and a mechanism for SDS-induced alpha-helical folding. This study demonstrates that, while the folding of peptides is mostly driven by hydrophobic effects, electrostatic interactions play a significant role in the formation and the stabilization of SDS-induced structure.

Amino Acid Sequence↗
PubMed1994

Electrostatic potential of the acetylcholine binding sites in the nicotinic receptor probed by reactions of binding-site cysteines with charged methanethiosulfonates.

All of the potent agonists and competitive antagonists of the acetylcholine receptors are positively charged, onium compounds. Among the interactions involved in the binding of these compounds, electrostatic forces undoubtedly make an important contribution. There is evidence that the acetylcholine binding site contains both acidic and aromatic amino acids. The acidic side chains could provide long-range charge-charge interactions with acetylcholine, while the aromatic side chains could provide short-range cation-pi-electron and hydrophobic interactions. To probe the long-range electrostatic interactions in the binding site, the rate constants for the reactions of sulfhydryl-specific reagents with cysteines in the binding site have been determined as a function of ionic strength. The reagents are the positively charged methanethiosulfonate ethylammonium and methanethiosulfonate ethyltrimethylammonium, the negatively charged methanethiosulfonate ethylsulfonate, and the neutral methyl methanethiosulfonate. In addition, the rate constants of the reactions of these methanethiosulfonates with positively charged, negatively charged, and uncharged simple thiol compounds have been similarly determined. An analysis of these rate constants in terms of absolute rate theory and Debye-Hückel theory is consistent with the acetylcholine binding site containing two to three negative charges and an electrostatic potential at zero ionic strength of about -80 mV relative to bulk solution.

Acetylcholine↗
PubMed1994

Evaluation of electrostatic and hydrophobic effects on the interaction of mitochondrial signal sequences with phospholipid bilayers.

The information that directs a nuclear-coded protein to be imported into mitochondria resides in an N-terminal extension, called a signal sequence. The primary sequences of all known ones differ. The only common feature is their ability to theoretically form an amphiphilic, positively charged, alpha-helix. We previously showed that a short stable helical segment was required for a peptide to be functional in import [Wang, Y., & Weiner, H. (1993) J. Biol. Chem. 268, 4759-4765]. Here we investigate the interaction of three altered signal sequences with phospholipid membranes containing cardiolipin to ascertain the importance of electrostatic and hydrophobic interactions with the membrane. The three already described peptides were derivatives of the signal sequence from aldehyde dehydrogenase, which is composed of three segments, two helices separated by a linker. ANCN had the C-helix replaced by the N-helix of the signal sequence of cytochrome c oxidase subunit IV, ANCC had the C-terminal helix replaced by the C-terminal random coil of cytochrome oxidase subunit IV, and linker deleted had the linker region deleted. ANCC, which functioned poorly as a signal sequence, had a very low affinity for binding to the negatively charged membranes. In contrast, both ANCN and linker deleted showed a relatively high affinity for the membranes and were capable of functioning as a good leader sequence. It appears that linker deleted possessed a stronger hydrophobic effect with membranes while ANCN had a higher electrostatic interaction. On the basic of these studies, a model was proposed to describe the interaction of mitochondrial signal sequences with negatively charged phospholipid membranes involving electrostatic interaction for initial binding and hydrophobic interaction for insertion.(ABSTRACT TRUNCATED AT 250 WORDS)

Aldehyde Dehydrogenase↗
PubMed1993

Contribution of long-range electrostatic interactions to the stabilization of the catalytic transition state of the serine protease subtilisin BPN'.

The possible role of long-range electrostatic interactions on the catalytic activity of the serine protease subtilisin BPN' is investigated using protein engineering techniques. Charged residues on the surface of the enzyme some 13-15 A from the active site were mutated to either neutral or oppositely charged residues. The effect of these mutations on the stability of a complex formed between subtilisin BPN' and Z-Ala-Ala-Pro-Phe-trifluoromethyl ketone, a transition-state inhibitor of the enzyme, was measured. The values of Ki for the complex between the trifluoromethyl ketone and wild-type and mutant subtilisins were used to study the possible contribution of long-range electrostatics in stabilizing the charge distribution in the complex and thus, by analogy, on the transition state of hydrolysis for subtilisin BPN'. Measurement of kon, koff, and Ki for the inhibition of wild-type and mutant subtilisins showed that charged mutations distant from the active site can affect koff and Ki but have little effect on kon. The experimental results show that there is a small, 0.10-0.46 kcal mol-1, but significant contribution to the binding energy from distant surface charges, at low ionic strength. The experimental results were compared to theoretical results, calculated using the DelPhi program for different charge distributions in the complex. The experimental results were found to be most consistent with a complex in which an ion pair is formed between the protonated active site histidine and the ionized oxyanion. Both experimental and theoretical results suggest that long-range electrostatic interactions do play a role in stabilizing the transition-state complex formed between enzyme and inhibitor.(ABSTRACT TRUNCATED AT 250 WORDS)

Bacillus↗
PubMed1994

Electrostatic effects in DNA triple helices.

Electrostatic effects dominate many aspects of nucleic acid behavior in a sequence independent manner. Sequence dependent electrostatic effects are introduced when a polypyrimidine, which contains one or more protonated cytosines, binds in the major groove (Hoogsteen side) of a complementary Watson-Crick double helix. Depending on the number of cytosines in the third strand (global effect) and on their relative position (local effect), the cytosines either enhance or decrease the binding affinity of the third strand, because adjacent protonated cytosines destabilize the third strand binding compared to cytosines separated by intervening thymines. This local effect (crowding) can reverse the effect of global composition. To investigate the extent of the local and global electrostatic effects further, two families of oligonucleotides have been synthesized. They share as a common design feature that they all fold sequentially into isosterical intramolecular triple helices by way of hairpin intermediates. This is confirmed by P1 nuclease probing, CD spectroscopy, and UV spectroscopy. The thermal stability of these conformations depends on the sequences, pH, and the ionic strength and can be summarized as follows: The energy of third strand binding depends on the protonated cytosine content in the Hoogsteen strand. It increases with increasing cytosine content (global composition) below pH 7.1 (150 mM Na+), decreases above pH 7.1, and is independent of the cytosine content at pH 7.1. At pH 6.75 the energy of binding increases with increasing cytosine content below 400 mM Na+, decreases above 400 mM Na+, and is independent of the global composition at 400 mM Na+.

Animals↗
PubMed1989

Redox protein electron-transfer mechanisms: electrostatic interactions as a determinant of reaction site in c-type cytochromes.

The effect of ionic strength on the rate constant for electron transfer has been used to determine the magnitude and charge sign of the net electrostatic potential which exists in close proximity to the sites of electron transfer on various c-type cytochromes. The negatively charged ferricyanide ion preferentially reacts at the positively charged exposed heme edge region on the front side of horse cytochrome c and Paracoccus cytochrome c2. In contrast, at low ionic strength, the positively charged cobalt phenanthroline ion interacts with the negatively charged back side of cytochrome c2, and at high ionic strength at a positively charged site on the front side of the cytochrome. With horse cytochrome c, over the ionic strength range studied, cobalt phenanthroline reacts only at a positively charged site which is probably not at the heme edge. These inorganic oxidants do not react at the relatively uncharged exposed heme edge sites on Azotobacter cytochrome c5 and Pseudomonas cytochrome c-551, but rather at a negatively charged site which is away from the heme edge. The results demonstrate that at least two electron-transferring sites on a single cytochrome can be functional, depending on the redox reactant used and the ionic strength. Electrostatic interactions between charge distributions on the cytochrome surface and the other reactant, or interactions involving uncharged regions on the protein(s), are critical in determining the preferred sites of electron transfer and reaction rate constants. When unfavorable electrostatic effects occur at a site near the redox center, less optimal sites at a greater distance can become kinetically important.

Acinetobacter↗
PubMed1981

Protein-protein interactions: nature of the electrostatic stabilization of deoxyhemoglobin tetramer formation.

The summed electrostatic free energy contributions to deoxyhemoglobin A0 tetramer formation were computed at a series of pH and ionic strength values as the difference between the computed values for the tetramer and for the sum of the four individual chains. The electrostatic stabilization of each monomer is similar and close to that for myoglobin. At ionic strength 0.10 M the electrostatic contribution to the stability of the tetramer is approximately 35 kcal/mol at pH 6.0 and 18 kcal/mol at pH 9.6. The specific contribution to the stabilization of the tetramer, (sigma delta G"i,el)tet, is obtained by difference and shows a broad plateau above 7 kcal/mol over the range from pH 6.0 to 8.0, which is nearly obliterated by pH 9.6. By examination of the contributions of individual sites under the above summation, it is found that sites in the alpha chains are responsible for virtually the entire stabilizing effects in tetramer formation. The major differences on tetramer formation are sensed at eight sites. The stabilization provided by four of these sites results simply from changes in solvent exposure of sites in the given monomers as the tetramer is assembled. They are offset in part by changes at three sites that sense the greatest destabilization and that are responsible for the near cancellation of effects among the beta-chain sites. The general implications for the stabilization of molecular assemblies are considered.

Calorimetry↗
PubMed1981

Electrostatic contributions to the energetics of dimer-tetramer assembly in human hemoglobin: pH dependence and effect of specifically bound chloride ions.

The pH dependence and effects of specifically bound chloride ions on the electrostatic contribution to the energetics of human hemoglobin dimer-tetramer assembly were computed for deoxy- and liganded hemoglobin. In the absence of bound chloride, the electrostatic contribution models the observed contrasting pH dependence of dimer-tetramer assembly for deoxy- and oxyhemoglobin. The effect of specifically bound chloride on the computations depends on the number and placement of the anions. Deoxy assembly shows a greater sensitivity to anion binding, with effects propagating as far as 32 A from the binding site. This sensitivity suggests a mechanism for electronic communication with the heme. At pH 7.4, 24-34% of the experimental value for deoxy and 73-85% for oxy dimer-tetramer assembly stabilization are predicted. Together with the findings of Chu and Ackers [Chu, A. H., & Ackers, G. K. (1981) J. Biol. Chem. 256, 1199] and other recent work, these results suggest that salt bridge formation is not the dominant energetic factor favoring deoxyhemoglobin dimer-tetramer assembly. Results of this work suggest that the marked electrostatic stabilization favoring oxy dimer-tetramer assembly may be a significant contributor to the quaternary enhancement observed in assembly reactions whereas the nonelectrostatic factors favoring deoxy dimer-tetramer assembly may be largely responsible for quaternary constraint.

Binding Sites↗
PubMed1979

Electrostatic effects in hemoglobin: Bohr effect and ionic strength dependence of individual groups.

The electrostatic treatment applied in the preceding paper in this issue [Matthew, J. B., Hanania, G.I.H., & Gurd, F.R.N. (1979) Biochemistry (preceding paper in this issue)] to the titration behavior of individual groups in human deoxyhemoglobin and oxyhemoglobin was applied to the computation of the alkaline Bohr effect at various values of ionic strength. The enhanced proton binding of deoxyhemoglobin in the pH range of 6--9 was accounted for at ionic strength 0.01 M by the effects of the unique charge distributions of ionizable groups in the two quaternary states. At ionic strength 0.10 M the effects of 2--4 bound anions had to be considered in addition in the deoxyhemoglobin charge configuration. At the higher ionic strength 10 groups per tetramer contributed to the Bohr effect, whereas 28 groups were contributory at the lower ionic strength. The ionic strength dependence of individual groups in the two tetrameric structures as well as in the alpha-chain monomer was explained in terms of the electrostatic treatment. This examination showed that the differences in electrostatic behavior of deoxy- and oxyhemoglobin follow from particular dissymmetries in their configurations with respect to charge and static solvent accessibility.

Electrochemistry↗