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At least 307 records · Page 17Linked to original sources
PubMed2006

Experimental/theoretical electrostatic properties of a styrylquinoline-type HIV-1 integrase inhibitor and its progenitors.

We have established that polyhydroxylated styrylquinolines are potent inhibitors of HIV-1 integrase (IN). Among them, we have identified (E)-8-hydroxy-2-[2-(4,5-dihydroxy-3-methoxyphenyl)-ethenyl]-7-quinolinecarboxylic acid (1) as a promising lead. Previous molecular dynamics simulations and docking procedures have shown that the inhibitory activity involves one or two metal cations (Mg2+), which are present in the vicinity of the active center of the enzyme. However, such methods are generally based on a force-field approach and still remain not as reliable as ab initio calculations with extended basis sets on the whole system. To go further in this area, the aim of the present study was to evaluate the predictive ability of the electron density and electrostatic properties in the structure-activity relationships of this class of HIV-1 antiviral drugs. The electron properties of the two chemical progenitors of 1 were derived from both high-resolution X-ray diffraction experiments and ab initio calculations. The twinning phenomenon and solvent disorder were observed during the crystal structure determination of 1. Molecule 1 exhibits a planar s-trans conformation, and a zwitterionic form in the crystalline state is obtained. This geometry was used for ab initio calculations, which were performed to characterize the electronic properties of 1. The electron densities, electrostatic potentials, and atomic charges of 1 and its progenitors are here compared and analyzed. The experimental and theoretical deformation density bond peaks are very comparable for the two progenitors. However, the experimental electrostatic potential is strongly affected by the crystal field and cannot straightforwardly be used as a predictive index. The weak difference in the theoretical electron densities between 1 and its progenitors reveals that each component of 1 conserves its intrinsic properties, an assumption reinforced by a 13C NMR study. This is also shown through an excellent correlation of the atomic charges for the common fragments. The electrostatic potential minima in zwitterionic and nonzwitterionic forms of 1 are discussed in relation with the localization of possible metal chelation sites.

Carbon Isotopes↗
PubMed2006

Molecular electrostatic potentials and hydrogen bonding in alpha-, beta-, and gamma-cyclodextrins.

Cyclodextrins (CDs) are cyclic oligomers of glucose having the toroid of sugars elaborating a central cavity of varying size depending on the number of glucoses. The central hydrophobic cavity of CD shows a binding affinity toward different guest molecules, which include small substituted benzenes to long chain surfactant molecules leading to a variety of inclusion complexes when the size and shape complementarity of host and guest are compatible. Further, interaction of guest molecules with the outer surface of alpha-CD has also been observed. Primarily it is the electrostatic interactions that essentially constitute a driving force for the formation of inclusion complexes. To gain insights for these interactions, the electronic structure and the molecular electrostatic potentials in alpha-, beta-, and gamma-CDs are derived using the hybrid density functional theory employing the three-parameter exchange correlation functional due to Becke, Lee, Yang, and Parr (B3LYP). The present work demonstrates how the topography of the molecular electrostatic potential (MESP) provides a measure of the cavity dimensions and understanding of the hydrogen-bonded interactions involving primary and secondary hydroxyl groups. In alpha-CD, hydrogen-bonded interactions between primary -OH groups engender a "cone-like" structure, while in beta- or gamma-CD the interactions from the primary -OH with ether oxygen in glucose ring facilitates a "barrel-like" structure. Further, the strength of hydrogen-bonded interactions of primary -OH groups follows the rank order alpha-CD > beta-CD > gamma-CD, while the secondary hydrogen-bonded interactions exhibit a reverse trend. Thus weak hydrogen-bonded interactions prevalent in gamma-CD manifest in shallow MESP minima near hydroxyl oxygens compared to those in alpha- or beta-CD. Furthermore, electrostatic potential topography reveals that the guest molecule tends to penetrate inside the cavity forming the inclusion complex in beta- or gamma-CD.

Computer Simulation↗
PubMed2004

Release of a dye from hydrogen-bonded and electrostatically assembled polymer films triggered by adsorption of a polyelectrolyte.

The absorption of dyes within hydrogen-bonded and electrostatically assembled multilayers and subsequent release of the dyes from the films were studied in situ using FTIR-ATR. Multilayers were composed of poly(methacrylic acid), PMAA, and poly(ethylene oxide), PEO (hydrogen-bonded multilayers), or of PMAA and 22% quarternized copolymer of N-ethyl-4-vinylpyridium bromide and 4-vinylpyridine, Q22 (electrostatically stabilized multilayers). After multilayer deposition, the solution pH was changed to produce excess charge within the films. Dyes with charge opposite to the excess charge of the film (Rhodamine 6G for hydrogen-bonded films or Bromophenol Blue for electrostatically assembled multilayers) were then allowed to absorb within multilayers. In both systems, the dyes were uniformly included within the films. The top layers largely affected the loading capacity of the multilayers, suggesting weaker binding of the dyes with the top layers. Dye release into a 0.01 M phosphate buffer was significantly smaller as compared to release in the presence of 0.05-0.5 mg/mL solutions of adsorbing polymers whose charge was the same as the excess charge within the films. We found that with the PMAA/PEO films, dye release did not depend on the concentration of polymer in solution, but was largely controlled by the amount of charge accumulated within the adsorbing polymer layer on the top of the film. For electrostatically stabilized PMAA/Q22 systems, dye release increased with increasing concentration of Q22 in solution, suggesting a significant contribution of the competition of solution species in the release mechanism. Our findings contribute to the understanding of interactions of small molecules with polymer multilayers and might have ramifications for novel applications of multilayer films as new materials for the controlled delivery of chemicals.

Journal Article↗
PubMed2006

Long-ranged electrostatic repulsion and crystallization of emulsion droplets in an ultralow dielectric medium supercritical carbon dioxide.

Electrostatic repulsion stabilizes micrometer-sized water droplets with spacings greater than 10 microm in an ultralow dielectric medium, CO2 (epsilon = 1.5), at elevated pressures. The morphology of the water/CO2 emulsion is characterized by optical microscopy and laser diffraction as a function of height. The counterions, stabilized with a nonionic, highly branched, stubby hydrocarbon surfactant, form an extremely thick double layer with a Debye screening length of 8.9 microm. As a result of the balance between electrostatic repulsion and the downward force due to gravity, the droplets formed a hexagonal crystalline lattice at the bottom of the high-pressure cell with spacings of over 10 microm. The osmotic pressure, calculated by solving the Poisson-Boltzmann equation in the framework of the Wigner-Seitz cell model, is in good agreement with that determined from the sedimentation profile measured by laser diffraction. Thus, the long-ranged stabilization of the emulsion may be attributed to electrostatic stabilization. The ability to form new types of colloids in CO2 with electrostatic stabilization is beneficial because steric stabilization is often unsatisfactory because of poor solvation of the stabilizers.

Journal Article↗
PubMedDate not supplied

Amazing stability of the arginine-phosphate electrostatic interaction.

Electrostatic interactions between a basic epitope containing adjacent arginine residues and an acidic epitope containing a phosphorylated serine are involved in receptor heteromerization. In the present study, we demonstrate that this arginine-phosphate electrostatic interaction possesses a "covalent-like" stability. Hence, these bonds can withstand fragmentation by mass spectrometric collision-induced dissociation at energies similar to those that fragment covalent bonds and they demonstrate an extremely low dissociation constant by plasmon resonance. The present work also highlights the importance of phosphorylation-dephosphorylation events in the modulation of this electrostatic attraction. Phosphorylation of the acidic epitope, a casein kinase one consensus site, makes it available to interact with the basic epitope. On the other hand, phosphorylation of serine and/or threonine residues adjacent to the basic epitope, a protein kinase A consensus site, slows down the attraction between the epitopes. Although analyzed here in the frame of receptor heteromerization, the arginine-phosphate electrostatic interaction most likely represents a general mechanism in protein-protein interactions.

Amino Acid Sequence↗
PubMed2002

Computational studies on biphenyl derivatives. Analysis of the conformational mobility, molecular electrostatic potential, and dipole moment of chlorinated biphenyl: searching for the rationalization of the selective toxicity of polychlorinated biphenyls (PCBs).

With the objective to understand how the pattern and degree of chlorination influence on the properties of the title molecules, a computational study on biphenyl and all the chlorinated biphenyls (from 1 to 10 chlorine atoms, 209 congeners) has been undertaken. The study includes conformational searches (and further refinement by molecular dynamics simulations) and the ab initio calculation of the molecular electrostatic potential (MEP) and the dipole moments for all the congeners. The most significant property is the MEP, finding a good correlation between the MEPs and the substitution pattern on chlorinated biphenyls. The most toxic congeners possess highly positive values of electrostatic potential on the aromatic rings and highly negative values of electrostatic potential on the chlorine atoms. Additionally, we have found that the toxic congeners possess conformations with low dipole moments, a fact that may be linked to the ready accumulation on the adipose tissue. The results on the geometry and electrostatic properties of chlorinated biphenyls can be useful to rationalize their selective toxicities.

Computer Simulation↗
PubMed1999

Electrostatic effects on the alpha-helix and beta-strand formation of BPTI(16-36) studied by Monte Carlo simulated annealing.

The electrostatic effects on the secondary structure forming tendencies of a peptide fragment with residues 16-36 of bovine pancreatic trypsin inhibitor, BPTI(16-36), are studied using Monte Carlo simulated annealing simulations. We consider three dielectric functions epsilon(r) of distance r: constant dielectric function (epsilon = 2; strong electrostatic interactions) and sigmoidal functions varying from epsilon(0) = 2 to epsilon(infinity) = 47 (intermediate) and to epsilon(infinity) = 78 (weak). Simulations with epsilon = 2 suggest that this peptide exhibits a significant propensity for beta-strand formations in accordance with a beta-sheet structure of the relevant segment in native BPTI. The tendency for alpha-helix formations becomes almost comparable with that of beta-strands in the simulation with epsilon(infinity) = 47, and there appears no appreciable conformational propensity for this case. Finally, the results with epsilon(infinity) = 78 generate low-energy conformations with conspicuous alpha-helices. These findings suggest the possibility that the change in electrostatic interactions can be the key factor for the conformational transitions of peptides between alpha-helix and beta-sheet that have recently been observed in experiments. These changes in electrostatic interactions can arise from those in various environmental factors such as conformations of the rest of the protein molecule and solvent conditions.

Algorithms↗
PubMedDate not supplied

Prediction of electrostatic effects of engineering of protein charges.

Accurate prediction of electrostatic effects on catalytic activity is an essential component of protein design. Site-directed mutagenesis of charged groups in subtilisin of Bacillus amyloliquefaciens has provided experimental measurements of electrostatic interactions which may be used to test such theoretical methods. The pKa of the histidine of the active site has been perturbed by +0.08 to -1.0 units by modifying one or two residues. Electrostatic effects in proteins can be modelled by the algorithm of Warwicker and Watson, which uses classical electrostatics and considers both the charge position and the shape of the molecule. Here we report that the algorithm can model several pKa shifts in subtilisin to fair accuracy.

Algorithms↗
PubMed1998

Effective electrostatic charge of coagulation factor X in solution and on phospholipid membranes: implications for activation mechanisms and structure-function relationships of the Gla domain.

Electrostatic interactions during activation of coagulation factor X were analysed by comparing effects of ionic strength on reaction rates with predictions of classical electrostatic theory. Geometrical correlations were investigated using alpha-shape-based computations on the crystal structure of Ca-fragment 1 of prothrombin. The ionic strength of the reaction environment was controlled with different univalent salts including NaCl, KCl, CsCl, LiCl, NaI, NaBr and KI. Reactions were assembled in three different environments: aqueous phase, cell membranes and synthetic TF/PS/PC (tissue factor relipidated in 30% phosphatidylserine, 70% phosphatidylcholine) vesicles. Reaction rates were measured at pH 7. 2, 4 mM CaCl2 and 33 degrees C, using chromogenic substrate to follow factor Xa generation. Rates decreased with increasing concentration of univalent salt, and the magnitude of the decrease was independent of salt type. On the basis of electrostatic relationships on PS/PC vesicles, the effective charge on factor X was +1.5, and the PS/factor X stoichiometry was 2.28. Structural analysis of the gamma-carboxyglutamic acid (Gla) domain revealed three surface pockets, forming potential sites for Ca2+ binding, with distinct spatial orientations. Interpreted together, the results of the geometric analysis and the measured effective charges suggest an efficient electrostatic mechanism for capture and retention of substrates by procoagulant membranes. Non-specific and delocalized interaction between the membrane and each one of the charged facets of the Gla domain can increase the probability of substrate binding, while allowing rotational and translational mobility of substrate for specific interaction with the enzyme.

Binding Sites↗
PubMed1999

Electrostatics in the active site of an alpha-amylase.

The importance of electrostatics in catalysis has been emphasized in the literature for a large number of enzymes. We examined this hypothesis for the Bacillus licheniformis alpha-amylase by constructing site-directed mutants that were predicted to change the pKa values of the catalytic residues and thus change the pH-activity profile of the enzyme. To change the pKa of the catalytic residues in the active site, we constructed mutations that altered the hydrogen bonding network, mutations that changed the solvent accessibility, and mutations that altered the net charge of the molecule. The results show that changing the hydrogen bonding network near an active site residue or changing the solvent accessibility of an active site residue will very likely result in an enzyme with drastically reduced activity. The differences in the pH-activity profiles for these mutants were modest. pH-activity profiles of mutants which change the net charge on the molecule were significantly different from the wild-type pH-activity profile. The differences were, however, difficult to correlate with the electrostatic field changes calculated. In several cases we observed that pH-activity profiles shifted in the opposite direction compared to the shift predicted from electrostatic calculations. This strongly suggests that electrostatic effects cannot be solely responsible for the pH-activity profile of the B. licheniformis alpha-amylase.

Bacillus↗
PubMed2005

Reliable treatment of electrostatics in combined QM/MM simulation of macromolecules.

A robust approach for dealing with electrostatic interactions for spherical boundary conditions has been implemented in the QM/MM framework. The development was based on the generalized solvent boundary potential (GSBP) method proposed by Im et al. [J. Chem. Phys. 114, 2924 (2001)], and the specific implementation was applied to the self-consistent-charge density-functional tight-binding approach as the quantum mechanics (QM) level, although extension to other QM methods is straightforward. Compared to the popular stochastic boundary-condition scheme, the new protocol offers a balanced treatment between quantum mechanics/molecular mechanics (QM/MM) and MM/MM interactions; it also includes the effect of the bulk solvent and macromolecule atoms outside of the microscopic region at the Poisson-Boltzmann level. The new method was illustrated with application to the enzyme human carbonic anhydrase II and compared to stochastic boundary-condition simulations using different electrostatic treatments. The GSBP-based QM/MM simulations were most consistent with available experimental data, while conventional stochastic boundary simulations yielded various artifacts depending on different electrostatic models. The results highlight the importance of carefully treating electrostatics in QM/MM simulations of biomolecules and suggest that the commonly used truncation schemes should be avoided in QM/MM simulations, especially in simulations that involve extensive conformational samplings. The development of the GSBP-based QM/MM protocol has opened up the exciting possibility of studying chemical events in very complex biomolecular systems in a multiscale framework.

Carbonic Anhydrases↗
PubMed2005

Intermolecular electrostatic energies using density fitting.

A method is presented to calculate the electron-electron and nuclear-electron intermolecular Coulomb interaction energy between two molecules by separately fitting the unperturbed molecular electron density of each monomer. This method is based on the variational Coulomb fitting method which relies on the expansion of the ab initio molecular electron density in site-centered auxiliary basis sets. By expanding the electron density of each monomer in this way the integral expressions for the intermolecular electrostatic calculations are simplified, lowering the operation count as well as the memory usage. Furthermore, this method allows the calculation of intermolecular Coulomb interactions with any level of theory from which a one-electron density matrix can be obtained. Our implementation is initially tested by calculating molecular properties with the density fitting method using three different auxiliary basis sets and comparing them to results obtained from ab initio calculations. These properties include dipoles for a series of molecules, as well as the molecular electrostatic potential and electric field for water. Subsequently, the intermolecular electrostatic energy is tested by calculating ten stationary points on the water dimer potential-energy surface. Results are presented for electron densities obtained at four different levels of theory using two different basis sets, fitted with three auxiliary basis sets. Additionally, a one-dimensional electrostatic energy surface scan is performed for four different systems (H2O dimer, Mg2+-H2O, Cu+-H2O, and n-methyl-formamide dimer). Our results show a very good agreement with ab initio calculations for all properties as well as interaction energies.

Computer Simulation↗
PubMed2006

Effective multipoles and Yukawa electrostatics in dressed molecule theory.

In this paper we derive the multipolar expansion of the screened Coulomb potential in electrolyte solutions with molecular solvent. The solute and solvent molecules can have arbitrary sizes, shapes, and internal charge distributions. We use the exact statistical mechanical definition of renormalized charge distributions coming from "dressed molecule theory" to determine the effective multipoles of a molecule immersed in an electrolyte. The effects of many-body correlations are fully included in our formally exact theory. We restrict ourselves to sufficiently dilute solutions so the screened Coulomb potential decays for large distances like a Yukawa function, exp(-kappa r)/r, where r is the distance and 1/kappa is the decay length (it is normally different from the Debye length). The resulting "Yukawa electrostatics" differ in many respects from ordinary, unscreened electrostatics. The "Yukawa charge" of a molecule (the lowest order moment in the multipolar expansion) is in general not equal to its Coulombic charge and it is not the integral of the renormalized charge distribution of the molecule. Moreover, as shown in this paper, the multipolar expansion of the Yukawa potential does not correspond, contrary to the case of the Coulomb potential, to its asymptotic expansion for large r. As a consequence, the charge term in the multipolar expansion is not the leading term in the asymptotic expansion. Instead, for large r values, multipoles of all orders contribute to the leading asymptotic term. Thus, the electrostatic potential from, for example, an electroneutral solvent molecule in an electrolyte solution has generally the same range as that from an ion. The proper asymptotic expansion for electrostatic interactions in electrolytes is derived. It is briefly shown how the multipole expansion formalism can also be applied in the Poisson-Boltzmann approximation for primitive model electrolytes.

Journal Article↗
PubMed1984

Model of specific complex between catabolite gene activator protein and B-DNA suggested by electrostatic complementarity.

Calculation of the electrostatic potential energy surfaces of Escherichia coli catabolite gene activator protein (CAP) dimer suggests a model for the complex between CAP and a specific DNA sequence. The positive electrostatic charge density of CAP lies on the two COOH-terminal domains and about 20-30 A from the molecular 2-fold axis. Assuming that the 2-fold axes of the CAP dimer and the DNA to which it binds are coincident, the positions of the positive electrostatic potential surfaces strongly suggest the rotational orientation of the DNA relative to the protein. A specific complex between CAP and its DNA binding site in the lac operon has been built with the DNA in this orientation. The amino ends of the two protruding F alpha-helices interact in successive major grooves of the DNA. Four side chains emanating from each F helix can form hydrogen bonds with the exposed edges of four bases in the major groove. Electrostatic considerations as well as the necessity to make interactions between CAP and a DNA site as much as 20 base pairs long require us to bend or kink the DNA. In our model of CAP complexed with B-DNA, as with those proposed for Cro and lambda cI repressors, the protruding second helices of the two-helix motif from both subunits interact in successive major grooves of B-DNA. However, unlike Cro and similar to lambda cI, the protruding alpha-helices are nearly parallel to the bases rather than the groove.

Amino Acid Sequence↗
PubMed1990

Hydroxyl hydrogen conformations in trypsin determined by the neutron diffraction solvent difference map method: relative importance of steric and electrostatic factors in defining hydrogen-bonding geometries.

Neutron diffraction maps have been used to assign the rotor conformations of the hydroxyl hydrogens in trypsin. Knowledge of these conformations is used to assess the relative importance of steric and electrostatic effects in conferring the H-bonding geometries of these groups. A general finding was that most hydroxyl groups are rotationally ordered with their highest populated conformation near the low-energy staggered orientation. For the low-energy conformers (-60 degrees, 60 degrees, 180 degrees) of serine and threonine, the trans (-180 degrees) position is most highly populated followed by +60 degrees. In trypsin, only 1 of 24 serines was found in the -60 degrees conformer. Serine hydroxyls preferentially act as H-bond acceptors and rarely are observed as H-bond donors alone. Threonines were found to be more likely than serines to participate in two H bonds; tryosines were found to prefer to act as donors. In H-bonding situations in which there was incompatibility between the energies defining the barrier to rotation and the local electrostatics, the electrostatic criteria dominated. Overall, the findings support a model of H bonding where there exists strong inherent complementarity between the low-energy hydroxyl orientations and the local electrostatic environment.

Hydrogen Bonding↗
PubMed1990

Electrostatic field around cytochrome c: theory and energy transfer experiment.

Energy transfer in the "rapid diffusion" limit from electronically excited terbium(III) chelates in three different charge states to horse heart ferricytochrome c was measured as a function of ionic strength. Theoretical rate constants calculated by numerical integration of the Forster integral (containing the Poisson-Boltzmann-generated protein electrostatic potential) were compared with the experimental data to evaluate the accuracy of protein electrostatic field calculations at the protein/solvent interface. Two dielectric formalisms were used: a simple coulombic/Debye-Hückel procedure and a finite difference method [Warwicker, J. & Watson, H. C. (1982) J. Mol. Biol. 157, 671-679] that accounts for the low-dielectric protein interior and the irregular protein/solvent boundary. Good agreement with experiment was obtained and the ionic-strength dependence of the reaction was successfully reproduced. The sensitivity of theoretical rate constants to the choices of effective donor sphere size and the energy transfer distance criterion was analyzed. Electrostatic potential and rate-constant calculations were carried out on sets of structures collected along two molecular dynamics trajectories of cytochrome c. Protein conformational fluctuations were shown to produce large variations in the calculated energy transfer rate constant. We conclude that protein fluctuations and the resulting transient structures can play significant roles in biological or catalytic activities that are not apparent from examination of a static structure. For calculating protein electrostatics, large-scale low-frequency conformational fluctuations, such as charged side-chain reorientation, are established to be as important as the computational method for incorporating dielectric boundary effects.

Animals↗
PubMed1992

A simple explanation of the electrostatics of the B-to-Z transition of DNA.

Whereas the phosphates of B-DNA jut out into the solution, those of Z-DNA, being closer to DNA matter, are less subject to electrostatic screening by counterions. We present simple planar models of B- and Z-DNA that reflect these geometric features. The ionic strength dependence of the difference in the Poisson-Boltzmann electrostatic free energy of the models agrees with that measured by Pohl [Pohl, F. M. (1983) Cold Spring Harbor Symp. Quant. Biol. 47, 113-118]. This indicates that the electrostatics of the B-to-Z transition are primarily controlled by a qualitative geometrical difference and not by details of the DNA geometry or by complex electrostatic properties of the ionic solution.

DNA↗
PubMed1993

An electrostatic mechanism for substrate guidance down the aromatic gorge of acetylcholinesterase.

Electrostatic calculations based on the recently solved crystal structure of acetylcholinesterase (acetylcholine acetylhydrolase, EC 3.1.1.7) indicate that this enzyme has a strong electrostatic dipole. The dipole is aligned with the gorge leading to its active site, so that a positively charged substrate will be drawn to the active site by its electrostatic field. Within the gorge, aromatic side chains appear to shield the substrate from direct interaction with most of the negatively charged residues that give rise to the dipole. The affinity of quaternary ammonium compounds for aromatic rings, coupled with this electrostatic force, may work in concert to create a selective and efficient substrate-binding site in acetylcholinesterase and explain why the active site is situated at the bottom of a deep gorge lined with aromatic residues.

Acetylcholinesterase↗