Wobble base-pairing in codon-anticodon interactions: a theoretical modelling study

The Crick wobble hypothesis attributes the phenomenon of codon degeneracy to a certain impreciseness of pairing between the third base of the codon and the first base of the anticodon. This theoretical study investigates the pairing properties of some wobble bases, including both, observed and unobserved pairs. Some wobble base-pairs are predicted to follow the Watson-Crick pairs in configuration and pairing facility, while others deviate from this norm. The observed U:V pair is unique in that a pairing configuration may be suggested for it wherein the hydrogen-bonding involves the exocyclic 5-carboxymethoxy group of V. By comparing the theoretical data on the configurations of these pairs with the evidence for their existence/non-existence in nature, some guidelines emerge for differentiating between observed and unobserved base pairs on the basis of the pairing configuration.     

Salicylic acid is not a bacterial siderophore: a theoretical study

Using a newly available program for calculating the concentrations and speciation of various ions (Pettit, LD & Powell KJ, `SolEq' Academic Software, 1999), we have calculated that at pH 7 the amount of free Fe(III) present in an aqueous solution is 1.4×10^–9 M and not 10^–18 M as is usually quoted. In the presence of salicylic acid, included in the calculations at 10^–4 M, the solubility of Fe(III) is increased to only 9.8×10^–9 M suggesting that salicylate is unable to act as a siderophore although it is produced as an extracellular product by several bacterial genera when grown iron deficiently. In the presence of 40 mM phosphate, the soluble Fe(III) concentration is decreased by 10⁴ at pH 7 and again this is hardly affected by the presence of salicylate. Thus, for microorganisms grown either in vitro or in vivo, salicylate is unlikely to function as a iron solubilizing agent. The same conclusions may also apply to 2,3-dihydroxybenzoic acid.     

Mechanism of mycolic acid cyclopropane synthase: a theoretical study

The reaction mechanism of mycolic acid cyclopropane synthase is investigated using hybrid density functional theory. The direct methylation mechanism is examined with a large model of the active site constructed on the basis of the crystal structure of the native enzyme. The important active site residue Glu140 is modeled in both ionized and neutral forms. We demonstrate that the reaction starts via the transfer of a methyl to the substrate double bond, followed by the transfer of a proton from the methyl cation to the bicarbonate present in the active site. The first step is calculated to be rate-limiting, in agreement with experimental kinetic results. The protonation state of Glu140 has a rather weak influence on the reaction energetics. In addition to the natural reaction, a possible side reaction, namely a carbocation rearrangement, is also considered and is shown to have a low barrier. Finally, the energetics for the sulfur ylide proposal, which has already been ruled out, is also estimated, showing a large energetic penalty for ylide formation.     

Lipid-mediated interactions between intrinsic membrane proteins: a theoretical study based on integral equations

This study of lipid-mediated interactions between proteins is based on a theory recently developed by the authors for describing the structure of the hydrocarbon chains in the neighborhood of a protein inclusion embedded in a lipid membrane [Lagüe et al., Farad. Discuss. 111:165-172, 1998]. The theory involves the hypernetted chain integral equation formalism for liquids. The exact lateral density-density response function of the hydrocarbon core, extracted from molecular dynamics simulations of a pure dipalmitoylphosphatidylcholine bilayer based on an atomic model, is used as input. For the sake of simplicity, protein inclusions are modeled as hard repulsive cylinders. Numerical calculations were performed with three cylinder sizes: a small cylinder of 2.5-A radius, corresponding roughly to an aliphatic chain; a medium cylinder of 5-A radius, corresponding to a alpha-helical polyalanine protein; and a large cylinder of 9-A radius, representing a small protein, such as the gramicidin channel. The calculations show that the average hydrocarbon density is perturbed over a distance of 20-25 A from the edge of the cylinder for every cylinder size. The lipid-mediated protein-protein effective interaction is calculated and is shown to be nonmonotonic. In the case of the small and the medium cylinders, the lipid-mediated effective interaction of two identical cylinders is repulsive at an intermediate range but attractive at short range. At contact, there is a free energy of -2k(B)T for the 2.5-A-radius cylinder and -9k(B)T for the 5-A-radius cylinder, indicating that the association of two alpha-helices of both sizes is favored by the lipid matrix. In contrast, the effective interaction is repulsive at all distances in the case of the large cylinder. Results were obtained with two integral equations theories: hypernetted chain and Percus-Yevick. For the two theories, all results are qualitatively identical.     

Exchange interactions in a Fe5 complex: A theoretical study using density functional theory

Theoretical methods based on density functional theory have been employed to analyze the exchange interactions in an Fe₅ complex. The calculated exchange coupling constants are consistent with an S = 15/2 ground state and agree well with those reported previously for other Fe^III polynuclear complexes. The strongest antiferromagnetic interactions are those through a double oxo-benzotriazole bridging ligand, where the benzotriazole ligand seems to play a minor role and the exchange coupling constants present values typical of single oxo bridging systems.     

Revealing substitution effects on the strength and nature of halogen-hydride interactions: a theoretical study

A quantum chemistry study was carried out to investigate the strength and nature of halogen bond interactions in HXeH···XCCY complexes, where X = Cl, Br and Y = H, F, Cl, Br, CN, NC, C₂H, CH₃, OH, SH, NH₂. Examination of the electrostatic potentials V(r) of the XCCY molecules reveals that the addition of substituents has a significant effect upon the most positive electrostatic potential on the surface of the interacting halogen atom. We found that the magnitude of atomic charges and multipole moments depends upon the halogen atom X and is rather sensitive to the electron-withdrawing/donating power of the remainder of the molecule. An excellent correlation was found between the most positive electrostatic potentials on the halogen atom and the interaction energies. For either HXeH···ClCCY or HXeH···BrCCY complexes, an approximate linear correlation between the interaction energies and halogens multipole moments are established, indicating that the electrostatic and polarization interactions are responsible for the stability of the complexes. According to energy decomposition analysis, it is revealed that the electrostatic interactions are the major source of the attraction in the HXeH···XCCY complexes. Furthermore, the changes in the electrostatic term are mainly responsible for the dependence of interaction energy on the halogen atom.

Urocanic acid as an efficient hydroxyl radical scavenger: a quantum theoretical study

The photoisomerization of urocanic acid (UCA)—which is present in human skin epidermis, where it acts as a sunscreen—from its trans isomer to its cis isomer upon exposure to UV-B radiation is known to cause immunosuppression. In recent years, the antioxidant properties of UCA (it acts as a hydroxyl radical scavenger) have also been recognized. In view of this, the mechanisms of stepwise reactions of trans-UCA with up to four hydroxyl radicals were investigated. The molecular geometries of the different species and complexes involved in the reactions (reactant, intermediate and product complexes, as well as transition states) were optimized via density functional theory in the gas phase. Solvation in aqueous media was treated with single point energy calculations using DFT and the polarizable continuum model. Single point energy calculations in the gas phase and aqueous media were also carried out using second-order Møller–Plesset perturbation theory (MP2). The AUG-cc-pVDZ basis set was employed in all calculations. Corrections for basis set superposition error (BSSE) were applied. Vibrational frequency analysis was performed for each optimized structure to ensure the validity of the optimized transition states. It was found that the binding of the first OH· radical to UCA involves a positive energy barrier, while subsequent reactions of OH· radicals are exergonic. Transition states were successfully located, even in those cases where the barrier energies were found to be negative. The cis–trans isomerization barrier energy of UCA and that of the first OH· radical addition to UCA are comparable, meaning that both processes can occur simultaneously. It was found that UCA could serve as an antioxidant in the form of an efficient OH· radical scavenger.     

A theoretical study of zinc(II) interactions with amino acid models and peptide fragments

Density functional theory calculations have been employed to study the interaction between the Zn²⁺ ion and some standard amino acid models. The highest affinities towards the Zn²⁺ ion are predicted for serine, cysteine, and histidine. Relatively high affinities are reported also for proline and glutamate/aspartate residues. It was found that the zinc complexes with cysteine adopt a tetrahedral conformation. Conversely, complexes with one or two histidine moieties remain in an octahedral geometry, while those with three or more histidine groups adopt a square-planar geometry. Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

Porphyrin-nucleic acid interactions: a review

Research involving three important interactions of synthetic cationic porphyrins with nucleic acids: DNA binding, oxidative-reductive strand scission and photosensitized strand scission, is examined retrospectively. The observation that these porphyrins as a class can associate with DNA by intercalative binding, outside binding and outside binding with self-stacking, i.e., the "three-mode binding model", is evaluated with regard to supporting data from several studies including recent evidence from NMR spectroscopy. Results from investigations into the "nuclease-like" activity of the metallo-derivatives of this class of porphyrins are surveyed for demonstrations of base specificity and the mechanism of the chemical interaction. The ability of cationic porphyrins to induce photosensitized damage in DNA is also reviewed with an emphasis on their strand scission activity via a singlet oxygen intermediate.     

A theoretical study of lipid-protein interactions in bilayers.

We present a theoretical study of the effect of different types of lipid-protein interactions on the thermodynamic properties of protein-containing lipid bilayers. The basis of this work is a theoretical model for pure lipid bilayer phase transitions developed earlier by Scott. Simple assumptions on the nature of the lipid conformations near a protein strongly affect the predicted properties of the model. Here we consider (a) random protein-lipid contacts, (b) enhanced contact between protein and lipid with a number of gauche bonds, and (c) enhanced contact between protein and all-trans but tilted lipid chains. Comparison of predicted results with experimental data seems to favor point c above but, by itself point c does not work well at larger protein concentrations. The results are discussed in the light of spectroscopic data, lipid-protein (plus annular lipid) miscibility, and interprotein forces.     

Contributions of long-range electrostatic interactions to 4-chlorobenzoyl-CoA dehalogenase catalysis: a combined theoretical and experimental study

It is well established that electrostatic interactions play a vital role in enzyme catalysis. In this work, we report theory-guided mutation experiments that identified strong electrostatic contributions of a remote residue, namely, Glu232 located on the adjacent subunit, to 4-chlorobenzoyl-CoA dehalogenase catalysis. The Glu232Asp mutant was found to bind the substrate analogue 4-methylbenzoyl-CoA more tightly than does the wild-type dehalogenase. In contrast, the kcat for 4-chlorobenzoyl-CoA conversion to product was reduced 10000-fold in the mutant. UV difference spectra measured for the respective enzyme-ligand complexes revealed an approximately 3-fold shift in the equilibrium of the two active site conformers away from that inducing strong pi-electron polarization in the ligand benzoyl ring. Increased substrate binding, decreased ring polarization, and decreased catalytic efficiency indicated that the repositioning of the point charge in the Glu232Asp mutant might affect the orientation of the Asp145 carboxylate with respect to the substrate aromatic ring. The time course for formation and reaction of the arylated enzyme intermediate during a single turnover was measured for wild-type and Glu232Asp mutant dehalogenases. The accumulation of arylated enzyme in the wild-type dehalogenase was not observed in the mutant. This indicates that the reduced turnover rate in the mutant is the result of a slow arylation of Asp145, owing to decreased efficiency in substrate nucleophilic attack by Asp145. To rationalize the experimental observations, a theoretical model is proposed, which computes the potential of mean force for the nucleophilic aromatic substitution step using a hybrid quantum mechanical/molecular mechanical method. To this end, the removal or reorientation of the side chain charge of residue 232, modeled respectively by the Glu232Gln and Glu232Asp mutants, is shown to increase the rate-limiting energy barrier. The calculated 23.1 kcal/mol free energy barrier for formation of the Meisenheimer intermediate in the Glu232Asp mutant represents an increase of 6 kcal/mol relative to that of the wild-type enzyme, consistent with the 5.6 kcal/mol increase calculated from the difference in experimentally determined rate constants. On the basis of the combination of the experimental and theoretical evidence, we hypothesize that the Glu232(B) residue contributes to catalysis by providing an electrostatic force that acts on the Asp145 nucleophile.     

Microbial diversity, producer-decomposer interactions and ecosystem processes: a theoretical model

Interactions between the diversity of primary producers and that of decomposers--the two key functional groups that form the basis of all ecosystems--might have major consequences on the functioning of depauperate ecosystems. I present a simple ecosystem model in which primary producers (plants) and decomposers (microbes) are linked through material cycling. The model considers a diversity of plant organic compounds and a diversity of microbial species. Nutrient recycling efficiency from organic compounds to decomposers is then the key parameter that controls ecosystem processes (primary productivity, secondary productivity, producer biomass and decomposer biomass). The model predicts that microbial diversity has a positive effect on nutrient recycling efficiency and ecosystem processes through either greater intensity of microbial exploitation of organic compounds or functional niche complementarity, much like in plants. Microbial niche breadth and overlap should not affect ecosystem processes unless they increase the number of organic compounds that are decomposed. In contrast, the model predicts that plant organic compound diversity can only have a negative effect or, at best, no effect on ecosystem processes, at least in a constant environment. This creates a tension between the effects of plant diversity and microbial diversity on ecosystem functioning, which may explain some recent experimental results.     

Structured modeling of a microbial system: I. A theoretical study of lactic acid fermentation

Most fermentation models presented in the literature are unstructured, i.e., the biomass composition is assumed constant during all operating conditions. These models are unable to simulate experiments carried out at widely different operating conditions. It is therefore interesting to examine simple structured models where knowledge of the cell physiology is taken into account in the modeling phase. In this article, a simple structured model is presented. The model is based on experimental work with the lactic acid bacteria Streptococcus cremoris, but due to the similarities in basic metabolism for many microorganisms it is applicable also for other fermentation system. The basic assumption in the model is that the biomass can be divided into two parts (compartments)-an active part and a mainly inactive structural part. The size of the active part has a pivotal role in the model.     

Binding of non-intercalating antibiotics to B-DNA: a theoretical study taking into account nucleic acid flexibility

A detailed theoretical study has been made for five antibiotics which all bind selectively to AT sequences in the minor groove of B-DNA: SN-18071, NSC-101327, distamycin-2, distamycin-3 and netropsin. The optimal complexes were found for systems in which the flexibility of DNA, as well as that of the antibiotics, was taken into account. Explicit, mobile counterions and a dielectric function modelling aqueous solution were also included. The binding geometries of the most strongly interacting antibiotics, distamycin-3 and netropsin, are compared in considerable detail and it is shown that notable differences exist between them. The results for netropsin are also discussed in the light of recent disagreements concerning its exact binding location within DNA.     

A theoretical study of electronic and structural states of neurotransmitters: gamma-aminobutyric acid and glutamic acid

As a first approach to understanding the mechanism for the recognition of a ligand by its receptor, we first calculated the electronic and structural states of ionized gamma-aminobutyric acid (GABA) and ionized glutamic acid using the ab initio method with the 6-311++G (3df, 2pd) basis set. We paid special attention to the physicochemical characteristics of these molecules, such as the electric dipole moment, electrostatic potential, and electrostatic force. Even though GABA and glutamic acid are known to exert completely opposite influences in the mammalian brain by binding their specific receptors, the only difference in their chemical structures is that glutamic acid contains one more carboxyl group than GABA. As a result, we succeeded in showing that a difference of only one carboxyl group induces significant differences in the electronic and structural states between these molecules. These differences have a crucial influence on the electric dipole moments, the electrostatic potentials, and the electrostatic forces. The most remarkable finding of the present research is that the electrostatic potential formed by glutamic acid is composed of only negative parts, while that formed by GABA is separated into positive and negative parts. These results strongly suggest that GABA can approach either positively or negatively charged amino acids by adjusting its own orientation, while glutamic acid can approach only a positively charged binding site.     

Aqueous solution interactions with sex hormone-binding globulin and estradiol: a theoretical investigation

Sex hormone-binding globulin (SHBG) is a binding protein that regulates the availability of steroid hormones in the plasma. Although best known as a steroid carrier, recent studies have associated SHBG in modulating behavioral aspects related to sexual receptivity. Among steroids, estradiol (17β-estradiol, oestradiol or E2), documented as the most active endogenous female hormone, exerts important physiological roles in both reproductive and non-reproductive functions. In this framework, we employed molecular dynamics (MD) and docking techniques for quantifying the interaction energy between a complex aqueous solution, composed by different salts, SHBG and E2. As glucose concentration resembles measured levels in diabetes, special emphasis was devoted to analyzing the interaction energy between this carbohydrate, SHBG and E2 molecules. The calculations revealed remarkable interaction energy between glucose and SHBG surface. Surprisingly, a movement of solute components toward SHBG was observed, yielding clusters surrounding the protein. The high energy and short distance between glucose and SHBG suggests a possible scenario in favor of a detainment state between the sugar and the protein. In this context, we found that glucose clustering does not insert modification on binding site area nor over binding energy SHBG-E2 complex, in spite of protein superficial area increment. The calculations also point to a more pronounced interaction between E2 and glucose, considering the hormone immersed in the solution. In summary, our findings contribute to a better comprehension of both SHBG and E2 interplay with aqueous solution components.     

Mode of action of intercalators: a theoretical study

Mode of action of some intercalators has been theoretically investigated on the basis of quantum mechanical perturbation method. Energies of H-bond interaction between drug chromophore and base pairs have been calculated in all possible orientations. The stacking energy has also been calculated with the base pairs. The effect of these interactions on specific recognition has also been discussed. On the basis of these studies, a model for the interaction of these drugs has been proposed. This explains the relative activities of acridine intercalators and satisfies the experimental observations.     

Spectroscopic investigations and hydrogen bond interactions of 8-aza analogues of xanthine, theophylline and caffeine: a theoretical study

The structure, spectral properties and the hydrogen bond interactions of 8-aza analogues of xanthine, theophylline and caffeine have been studied by using quantum chemical methods. The time-dependent density functional theory (TD-DFT) and the singly excited configuration interaction (CIS) methods are employed to optimize the excited state geometries of isolated 8-azaxanthine, 8-azatheophylline tautomers and 8-azacaffeine in both the gas and solvent phases. The solvent phase calculations are performed using the polarizable continuum model (PCM). The absorption and emission spectra are calculated using the time-dependent density functional theory (TD-DFT) method. The results from the TD-DFT calculations reveal that the excitation spectra are red shifted relative to absorption in aqueous medium. These changes in the transition energies are qualitatively comparable to the experimental data. The examination of molecular orbital reveals that the molecules with a small H→L energy gap possess maximum absorption and emission wavelength. The relative stability and hydrogen bonded interactions of mono and heptahydrated 8-azaxanthine, 8-azatheophylline tautomers and 8-azacaffeine have been studied using the density functional theory (DFT) and Møller Plesset perturbation theory (MP2) implementing the 6-311++G(d,p) basis set. The formation of strong N-H…O bond has resulted in the highest interaction energy among the monohydrates. Hydration does not show any significant impact on the stability of heptahydrated complexes. The atoms in molecule (AIM) and natural bonding orbital (NBO) analyses have been performed to elucidate the nature of the hydrogen bond interactions in these complexes.

Cooperative effect of water molecules in the self-catalyzed neutral hydrolysis of isocyanic acid: a comprehensive theoretical study

The detailed reaction mechanism for the water-assisted hydrolysis of isocyanic acid, HNCO + (n + 1) H₂O → CO₂ + NH₃ + nH₂O (n = 0−6), taking place in the gas phase, has been investigated. All structures were optimized and characterized at the MP2/6-31 + G* level of theory, and then re-optimized at MP2/6-311++G**. The seven explicit water molecules participating in the hydrolysis can be divided into two groups, one directly involved in the proton relay, and the other located in the vicinity of the substrate playing the cooperative role by engaging in hydrogen-bonding to HN = C = O. Two possible reaction pathways, the addition of water molecule across the C = N bond or across the C = O bond, are discussed, and the former is proved to be more favorable energetically. Our calculations suggest that, in the most kinetically favorable pathway for the titled hydrolysis, three water molecules are directly participating in the hydrogen transfer via an eight-membered cyclic transition state, while the other four water molecules catalyze the hydrolysis of HN = C = O by forming three eight-membered cooperative loops near the substrate. This strain-free hydrogen-bond network leads to the best estimated rate-determining activation energy of 24.9 kJ mol⁻¹ at 600 K, in excellent agreement with the gas-phase kinetic experimental result, 25.8 kJ mol⁻¹.     

A theoretical study on the hydrogen-bonding interactions between flavonoids and ethanol/water

Ethanol and water are the solvents most commonly used to extract flavonoids from propolis. Do hydrogen-bonding interactions exist between flavonoids and ethanol/water? In this work, this question was addressed by using density functional theory (DFT) to provide information on the hydrogen-bonding interactions between flavonoids and ethanol/water. Chrysin and Galangin were chosen as the representative flavonoids. The investigated complexes included chrysin–H₂O, chrysin–CH₃CH₂OH, galangin–H₂O and galangin–CH₃CH₂OH dyads. Molecular geometries, hydrogen-bond binding energies, charges of monomers and dyads, and topological analysis were studied at the B3LYP/M062X level of theory with the 6?31++G(d,p) basis set. The main conclusions were: (1) nine and ten optimized hydrogen-bond geometries were obtained for chrysin–H₂O/CH₃CH₂OH and galangin–H₂O/CH₃CH₂OH complexes, respectively. (2) The hydrogen atoms except aromatic H1 and H5 and all of the oxygen atoms can form hydrogen-bonds with H₂O and CH₃CH₂OH. Ethanol and water form strong hydrogen-bonds with the hydroxyl, carbonyl and ether groups in chrysin/galangin and form weak hydrogen-bonds with aromatic hydrogen atoms. Except in structures labeled A and B, chrysin and galangin interact more strongly with H₂O than CH₃CH₂OH. (3) When chrysin and galangin form hydrogen-bonds with H₂O and CH₃CH₂OH, charge transfers from the hydrogen-bond acceptor (H₂O and CH₃CH₂OH in structures A, B, G, H, I, J) to the hydrogen-bond donor (chrysin and galangin in structure A, B, G, H, I, J). The stronger hydrogen-bond makes the hydrogen-bond donor lose more charge (A> B> G> H> I> J). (4) Most of the hydrogen-bonds in chrysin/galangin?H₂O/CH₃CH₂OH complexes may be considered as electrostatic dominant, while C?O2···H in structures labeled E and C?O5···H in structures labeled J are hydrogen-bonds combined of electrostatic and covalent characters. H9, H7, and O4 are the preferred hydrogen-bonding sites.