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PubMed2005

Electrostatic repulsion, compensatory mutations, and long-range non-additive effects at the dimerization interface of the HIV capsid protein.

In previous studies, thermodynamic dissection of the dimerization interface in CA-C, the C-terminal domain of the capsid protein of human immunodeficiency virus type 1, revealed that individual mutation to alanine of Ser178, Glu180, Glu187 or Gln192 led to significant increases in dimerization affinity. Four related aspects derived from this observation have been now addressed, and the results can be summarized as follows: (i) thermodynamic analyses indicate the presence of an intersubunit electrostatic repulsion between both Glu180 residues. (ii) The mutation Glu180 to Ala was detected in nearly all type 2 human immunodeficiency virus variants, and in several simian immunodeficiency viruses analyzed. However, this mutation was strictly co-variant with mutations Ser178Asp in a neighboring residue, and Glu187Gln. Thermodynamic analysis of multiple mutants showed that Ser178Asp compensated, alone or together with Glu187Gln, the increase in affinity caused by the mutation Glu180Ala, and restored a lower dimerization affinity. (iii) The increase in the affinity constant caused by the multiple mutation to Ala of Ser178, Glu180, Glu187 and Gln192 was more than one order of magnitude lower than predicted if additivity were present, despite the fact that the 178/180 pair and the two other residues were located more than 10A apart. (iv) Mutations in CA-C that caused non-additive increases in dimerization affinity also caused a non-additive increase in the capacity of the isolated CA-C domain to inhibit the assembly of capsid-like HIV-1 particles in kinetic assays. In summary, the study of a protein-protein interface involved in the building of a viral capsid has revealed unusual features, including intersubunit electrostatic repulsions, co-variant, compensatory mutations that may evolutionarily preserve a low association constant, and long-range, large magnitude non-additive effects on association.

Binding Sites↗

PubMed2006

Electrostatic interactions in the denatured state and in the transition state for protein folding: effects of denatured state interactions on the analysis of transition state structure.

The development of electrostatic interactions during the folding of the N-terminal domain of the ribosomal protein L9 (NTL9) is investigated by pH-dependent rate equilibrium free energy relationships. We show that Asp8, among six acidic residues, is involved in non-native, electrostatic interactions with K12 in the transition state for folding as well as in the denatured state. The perturbed native state pK(a) of D8 (pK(a) = 3.0) appears to be maintained through non-native interactions in both the transition state and the denatured state. Mutational effects on the stability of the transition state for protein (un)folding are often analyzed in respect to change in ground states. Thus, the interpretation of transition state analysis critically depends on an understanding of mutational effects on both the native and denatured state. Increasing evidence for structurally biased denatured states under physiological conditions raises concerns about possible denatured state effects on folding studies. We show that the structural interpretation of transition state analysis can be altered dramatically by denatured state effects.

Hydrogen-Ion Concentration↗

PubMed2005

Quantitative study of electrostatic and steric effects on physicochemical property and biological activity.

The physicochemical properties and biological activities are highly dependent on the electrostatic and steric effects of compounds. The characterization of these structural features will help to elucidate the quantitative structure-property/activity relationship (QSPR/QSAR). In this paper, two novel structural descriptors, lone-pair electrons index (LEI) and molecular volume index (MVI) were developed to quantify the molecular electrostatic and steric effects, respectively. One of the most attractive traits of these two descriptors is that the calculation is very easy, especially for LEI, which only takes the heteroatoms into account. Four data sets on diverse physicochemical properties and biological activities were selected as examples to evaluate the utility of these descriptors. One or two-variable multiple linear regression (MLR) models against the four data sets obtained such correlation results as follows: correlation coefficient R = 0.9998 and standard deviation s = 0.095 for the partition coefficient of halide benzenes; R = 0.9689 and s = 0.248 for the toxicity of heterocyclic nitrogen-containing compounds to miracidium; R = 0.9645 and s = 0.209 for the antifungal activity of benzyl alcohols to aspergillus niger; R = 0.9530 and s = 0.206 for the toxicity of substituted phenols against tetrahymena pyriformis. Leave-one-out cross validation was also carried out to evaluate the stability of each model and good results were obtained.

Animals↗

PubMed2006

Differences in electrostatic potential around DNA fragments containing adenine and 8-oxo-adenine. An analysis based on regular cylindrical projection.

Changes of electrostatic potential (EP) around the DNA molecule resulting from chemical modifications of nucleotides may play a role in enzymatic recognition of damaged sites. Effects of chemical modifications of nucleotides on the structure of DNA have been characterized through large scale density functional theory computations. Quantum mechanical structural optimizations of DNA fragments with three pairs of nucleotides and accompanying counteractions were performed with a B3LYP exchange-correlation functional and 6-31G(d,p) basis sets. The "intact" DNA fragment contained adenine in the middle layer, while the "damaged" fragment had the adenine replaced with 8-oxo-adenine. The electrostatic potential around these DNA fragments was projected on a cylindrical surface around the double helix. The two-dimensional maps of EP of the intact and damaged DNA fragments were analyzed to identify these modifications of EP that result from the occurrence of 8-oxo-adenine (8oA). It was found that distortions of a phosphate group neighboring 8oA and displacements of the accompanying countercation are clearly reflected in the EP maps.

Adenine↗

PubMed2006

Mapping electrostatic potential of a protein on its hydrophobic surface: implications for crystallization of Cytochrome P450scc.

Calculation and combined visualization of electrostatic and hydrophobic properties of Cytochrome P450scc based on two very different homology models allowed to identify extensive hydrophobic patches with neutral electrostatic potential and mutations removing such patches and thus expecting to facilitate crystallization of Cytochrome P450scc, especially for the nanotemplate crystallization method. Implications are discussed for optimizing crystallization and other aspects of protein surface properties and protein recognition.

Animals↗

PubMed2005

Consecutive monitoring of lifelong production of conidia by individual conidiophores of Blumeria graminis f. sp. hordei on barley leaves by digital microscopic techniques with electrostatic micromanipulation.

Conidial formation and secession by living conidiophores of Blumeria graminis f. sp. hordei on barley leaves were consecutively monitored using a high-fidelity digital microscopic technique combined with electrostatic micromanipulation to trap the released conidia. Conidial chains formed on conidiophores through a series of septum-mediated division and growth of generative cells. Apical conidial cells on the conidiophores were abstricted after the conidial chains developed ten conidial cells. The conidia were electrically conductive, and a positive charge was induced in the cells by a negatively polarized insulator probe (ebonite). The electrostatic force between the conidia and the insulator was used to attract the abstricted conidia from the conidiophores on leaves. This conidium movement from the targeted conidiophore to the rod was directly viewed under the digital microscope, and the length of the interval between conidial septation and secession, the total number of the conidia produced by a single conidiophore, and the modes of conidiogenesis were clarified. During the stage of conidial secession, the generative cells pushed new conidial cells upwards by repeated division and growth. The successive release of two apical conidia was synchronized with the successive septation and growth of a generative cell. The release ceased after 4-5 conidia were released without division and growth of the generative cell. Thus, the life of an individual conidiophore (from the erection of the conidiophore to the release of the final conidium) was shown to be 107 h and to produce an average of 33 conidia. To our knowledge, this is the first report on the direct estimation of life-long conidial production by a powdery mildew on host leaves.

Ascomycota↗

PubMed2005

Conventional and back-side focused ion beam milling for off-axis electron holography of electrostatic potentials in transistors.

Off-axis electron holography is used to characterize a linear array of transistors, which was prepared for examination in cross-sectional geometry in the transmission electron microscope (TEM) using focused ion beam (FIB) milling from the substrate side of the semiconductor device. The measured electrostatic potential is compared with results obtained from TEM specimens prepared using the more conventional 'trench' FIB geometry. The use of carbon coating to remove specimen charging effects, which result in electrostatic fringing fields outside 'trench' specimens, is demonstrated. Such fringing fields are not observed after milling from the substrate side of the device. Analysis of the measured holographic phase images suggests that the electrically inactive layer on the surface of each FIB-milled specimen typically has a thickness of 100 nm.

Journal Article↗

PubMed2006

A femtogram resolution mass sensor platform, based on SOI electrostatically driven resonant cantilever. Part I: electromechanical model and parameter extraction.

A microcantilever based platform for mass detection in the femtogram range has been integrated in the doped top silicon layer of a SOI substrate. The on-plane fundamental resonance mode of the cantilever is excited electrostatically and detected capacitively by means of two parallel placed electrodes in a two port configuration. An electromechanical model of the cantilever-electrodes transducer and its implementation in a SPICE environment are presented. The model takes into account non-linearities from variable cantilever-electrode gap, fringing field contributions and real deflection shape of the cantilever for the calculation of the driving electrostatic force. A fitting of the model to the measured S(21) transmitted power frequency response is performed to extract the characteristic sensor parameters as Young modulus, Q factor, electrical parasitics and mass responsivity.

Journal Article↗

PubMed2002

Effect of liposome charge and PEG polymer layer thickness on cell-liposome electrostatic interactions.

Targeted drug delivery requires binding to (and subsequent uptake by) the carrier and target cell. In this paper, we calculate the work required to bring into contact liposomal carriers and cells as a function of the liposome and cell electrostatic characteristics. We find that cell-liposome adhesion is sensitive to the cell type and optimized at a cell to liposome charge ratio which depends on the degree of cell charge regulation. As a result, uptake (which is dependent on the occurrence of binding) is also optimized. Incorporation of a (poly)ethylene glycol (PEG) layer enhances liposome adhesion in cases where the cell-liposome interactions are repulsive, and suppresses adhesion in systems where the interactions are attractive. Our results, which are in agreement with experimental observations, show that electrostatic interactions may be designed to enable targeted drug delivery by liposomes to a specific cell population.

Cell Adhesion↗

PubMed1997

Electrostatic parameters of cationic liposomes commonly used for gene delivery as determined by 4-heptadecyl-7-hydroxycoumarin.

UNLABELLED: Cationic liposomes are used to deliver genes into cells in vitro and in vivo. The present study is aimed to characterize the electrostatic parameters of cationic, large unilamellar vesicles, 110 +/- 20 nm in size, composed of DOTAP/DOPE (mole ratio 1/1), DOTAP/DOPC (mole ratio 1/1), 100% DOTAP, DMRIE/DOPE 1/1, or DC-CHOL/DOPE (mole ratio 1/1). { ABBREVIATIONS: DOTAP, N-(1-(2,3-dioleoyloxy)propyl)-N,N,N-trimethylammonium chloride; DOPE, 1,2-dioleoyl-sn-glycero-3-phosphatidylethanolamine; DOPC, 1,2-dioleoyl-sn-glycero-3-phosphatidylcholine; DMRIE, 1,2-dimyristyloxypropyl-3-dimethyl-hydroxyethylammonium bromide; DC-CHOL, 3beta[N-(N',N'-dimethylaminoethane)carbamoyl]cholesterol}. The cationic liposomes had a large positive surface potential and a high pH at the liposomal surface in 20 mM Hepes buffer (pH 7.4) as monitored by the pH-sensitive fluorophore 4-heptadecyl-7-hydroxycoumarin. In contrast to DOTAP and DMRIE which were 100% charged, DC-CHOL in DC-CHOL/DOPE (1/1) liposomes was only about 50% charged in 20 mM Hepes buffer (pH 7.4). This might result in an easier dissociation of bilayers containing DC-CHOL from the plasmid DNA (which is necessary to enable transcription), in a decrease of the charge on the external surfaces of the liposomes or DNA-lipid complexes, and in an increase in release of the DNA-lipid complex into the cytosol from the endosomes. Other electrostatic characteristics found were that the primary amine group of DOPE in cationic liposomes dissociated at high (> 7.9) pHbulk and that a salt bridge was likely between the quaternary amine of DOTAP or DMRIE and the phosphate group of DOPE or DOPC, but not between the tertiary amine of DC-CHOL and the phosphate group of DOPE. The liposomes containing DOTAP were unstable upon dilution, probably due to the high critical aggregation concentration of DOTAP, 7 X 10(-5) M. This might also be a mechanism of the dissociation of bilayers containing DOTAP from the plasmid DNA.

Cholesterol↗

PubMed1998

Electrostatic and structural properties of complexes involving plasmid DNA and cationic lipids commonly used for gene delivery.

UNLABELLED: The present study is aimed to characterize the interactions between plasmid DNA and cationic, large unilamellar vesicles, 110+/-20nm in size, composed of lipids commonly used for transfections including DOTAP/DOPE (mole ratio 1/1), DOTAP/DOPC (mole ratio 1/1), 100% DOTAP, or DC-CHOL/DOPE (mole ratio 1/1). [ ABBREVIATIONS: DOTAP, N-(1-(2,3-dioleoyloxy)propyl)-N,N,N-trimethylammonium chloride; DOPE, 1,2-dioleoyl-sn-glycero-3-phosphatidylethanolamine; DOPC, 1,2-dioleoyl-sn-glycero-3-phosphatidylcholine; DC-CHOL, 3 beta-[N-(N',N'-dimethylaminoethane)carbamoyl] cholesterol]. A novel approach of combining Gouy-Chapman calculations and fluorescence measurements of the pH at the surface of lipid assemblies by the fluorophore 4-heptadecyl-7-hydroxycoumarin showed that electrostatic parameters played a key role in the instantaneous formation of the DNA-lipid complexes upon addition of different amounts of plasmid DNA to cationic liposomes in 20 mM Hepes buffer (pH 7.4). Addition of large amounts of plasmid DNA leads to neutralization of 60% of the protonated DC-CHOL in DC-CHOL/DOPE (1/1) assemblies and 80% of the DOTAP in lipid assemblies. The characterization of these electrostatic parameters of the complexes suggests better and closer surrounding of plasmid DNA by lipids when DOPE is present. Time-dependent static light-scattering measurements monitored the formation of complexes and also showed that these complexes were highly unstable with respect to size at DNA/cationic lipid molar ratios between 0.2 and 0.8.

Cations↗

PubMed1999

Effects of electrostatic interaction on the phase stability and structures of cubic phases of monoolein/oleic acid mixture membranes.

To elucidate effects of electrostatic interactions due to the surface charges on structures and phase stability of cubic phases of lipids, the mixture membranes of monoolein (MO) and oleic acid (OA) (OA/MO membrane) have been investigated by small-angle X-ray scattering method. As increasing OA concentration in the OA/MO membrane, a phase transition from Q(224) to Q(229) phase occurred, and above 1.0 mol% OA, OA/MO membranes were in the Q(229) phase. However, when NaCl concentration in the bulk phase is large, the Q(224) phase is more stable than the Q(229) phase in the OA/MO membranes containing high concentrations of OA. These results indicate that the electrostatic repulsion between the headgroups of these membranes makes the Q(229) phase more stable than the Q(224) phase. We have also found that lowering pH induces a phase transition from Q(229) to Q(224), and at lower pH a phase transition from Q(224) to H(II). These results are discussed in terms of the spontaneous curvature of the monolayer membrane and a lipid packing parameter of the membrane.

Glycerides↗

PubMed2000

Electrostatic interactions regulate desensitization of the nicotinic acetylcholine receptor.

To determine the importance of electrostatic interactions for agonist binding to the nicotinic acetylcholine receptor (AChR), we examined the affinity of the fluorescent agonist dansyl-C6-choline for the AChR. Increasing ionic strength decreased the binding affinity in a noncompetitive manner and increased the Hill coefficient of binding. Small cations did not compete directly for dansyl-C6-choline binding. The sensitivity to ionic strength was reduced in the presence of proadifen, a noncompetitive antagonist that desensitizes the receptor. Moreover, at low ionic strength, the dansyl-C6-choline affinities were similar in the absence or presence of proadifen, a result consistent with the receptor being desensitized at low ionic strength. Similar ionic strength effects were observed for the binding of the noncompetitive antagonist [(3)H]ethidium when examined in the presence and absence of agonist to desensitize the AChR. Therefore, ionic strength modulates binding affinity through at least two mechanisms: by influencing the conformation of the AChR and by electrostatic effects at the binding sites. The results show that charge-charge interactions regulate the desensitization of the receptor. Analysis of dansyl-C6-choline binding to the desensitized conformation using the Debye-Hückel equation was consistent with the presence of five to nine negative charges within 20 A of the acetylcholine binding sites.

Animals↗

PubMed2001

Stretching single-stranded DNA: interplay of electrostatic, base-pairing, and base-pair stacking interactions.

Recent single-macromolecule observations revealed that the force/extension characteristics of single-stranded DNA (ssDNA) are closely related to solution ionic concentration and DNA sequence composition. To understand this, we studied the elastic property of ssDNA through the Monte Carlo implementation of a modified freely jointed chain (FJC), with electrostatic, base-pairing, and base-pair stacking interactions all incorporated. The simulated force-extension profiles for both random and designed sequences have attained quantitative agreements with the experimental data. In low-salt solution, electrostatic interaction dominates, and at low forces, the molecule can be more easily aligned than an unmodified FJC. In high-salt solution, secondary hairpin structure appears in ssDNA by the formation of base pairs between complementary bases, and external stretching causes a hairpin-coil structural transition, which is continuous for ssDNA made of random sequences. In designed sequences such as poly(dA-dT) and poly(dG-dC), the stacking potential between base pairs encourages the aggregation of base pairs into bulk hairpins and makes the hairpin-coil transition a discontinuous (first-order) process. The sensitivity of elongation to the base-pairing rule is also investigated. The comparison of modeling calculations and the experimental data suggests that the base pairing of single-stranded polynucleotide molecules tends to form a nested and independent planar hairpin structure rather than a random intersecting pattern.

Base Pairing↗

PubMed2001

Electrostatic analysis and Brownian dynamics simulation of the association of plastocyanin and cytochrome f.

The oxidation of cytochrome f by the soluble cupredoxin plastocyanin is a central reaction in the photosynthetic electron transfer chain of all oxygenic organisms. Here, two different computational approaches are used to gain new insights into the role of molecular recognition and protein-protein association processes in this redox reaction. First, a comparative analysis of the computed molecular electrostatic potentials of seven single and multiple point mutants of spinach plastocyanin (D42N, E43K, E43N, E43Q/D44N, E59K/E60Q, E59K/E60Q/E43N, Q88E) and the wt protein was carried out. The experimentally determined relative rates (k(2)) for the set of plastocyanin mutants are found to correlate well (r(2) = 0.90 - 0.97) with the computed measure of the similarity of the plastocyanin electrostatic potentials. Second, the effects on the plastocyanin/cytochrome f association rate of these mutations in the plastocyanin "eastern site" were evaluated by simulating the association of the wild type and mutant plastocyanins with cytochrome f by Brownian dynamics. Good agreement between the computed and experimental relative rates (k(2)) (r(2) = 0.89 - 0.92) was achieved for the plastocyanin mutants. The results obtained by applying both computational techniques provide support for the fundamental role of the acidic residues at the plastocyanin eastern site in the association with cytochrome f and in the overall electron-transfer process.

Computer Simulation↗

PubMed2002

Continuum electrostatics fails to describe ion permeation in the gramicidin channel.

We investigate the validity of continuum electrostatics in the gramicidin A channel using a recently determined high-resolution structure. The potential and electric field acting on ions in and around the channel are computed by solving Poisson's equation. These are then used in Brownian dynamics simulations to obtain concentration profiles and the current passing through the channel. We show that regardless of the effective dielectric constant used for water in the channel or the channel protein, it is not possible to reproduce all the experimental data on gramicidin A; thus, continuum electrostatics cannot provide a valid framework for the description of ion dynamics in gramicidin channels. Using experimental data and molecular dynamics simulations as guides, we have constructed potential energy profiles that can satisfactorily describe the available physiological data. These profiles provide useful benchmarks for future potential of mean force calculations of permeating ions from molecular dynamics simulations of gramicidin A. They also offer a convenient starting point for studying structure-function relationships in modified gramicidin channels.

Biophysical Phenomena↗

PubMed2002

Bridging implicit and explicit solvent approaches for membrane electrostatics.

Conformations of a zwitterionic bilayer were sampled from a molecular dynamics simulation and their electrostatic properties analyzed by solution of the Poisson equation. These traditionally implicit electrostatic calculations were performed in the presence of varying amounts of explicit solvent to assess the magnitude of error introduced by a uniform dielectric description of water surrounding the bilayer. It was observed that membrane dipole potential calculations in the presence of explicit water were significantly different than wholly implicit solvent calculations with the calculated dipole potential converging to a reasonable value when four or more hydration layers were included explicitly.

Algorithms↗

PubMed2002

Intramembrane electrostatic interactions destabilize lipid vesicles.

Membrane stability is of central concern in many biology and biotechnology processes. It has been suggested that intramembrane electrostatic interactions play a key role in membrane stability. However, due primarily to a lack of supporting experimental evidence, they are not commonly considered in mechanical analyses of lipid membranes. In this paper, we use the micropipette aspiration technique to characterize the elastic moduli and critical tensions of lipid vesicles with varying surface charge. Charge was induced by doping neutral phosphatidylcholine vesicles with anionic lipids phosphatidylglycerol and phosphatidic acid. Measurements were taken in potassium chloride (moderate ion-lipid binding) and tetramethylammonium chloride (low ion-lipid binding) solutions. We show that inclusion of anionic lipid does not appreciably alter the areal dilation elasticity of lipid vesicles. However, the tension required for vesicle rupture decreases with increasing anionic lipid fraction and is a function of electrolyte composition. Using vesicles with 30% charged (i.e., unbound) anionic lipid, we measured critical tension reductions of 75%, demonstrating the important role of electrostatic interactions in membrane stability.

Biophysical Phenomena↗