Anti-insulin antibody structure and conformation. II. Molecular dynamics with explicit solvent.

Molecular dynamics at 300 K was used as a conformation searching tool to analyze a knowledge-based structure prediction of an anti-insulin antibody. Solvation effects were modeled by packing water molecules around the antigen binding loops. Some loops underwent backbone and side-chain conformational changes during the 95-ps equilibration, and most of these new, lower potential energy conformations were stable during the subsequent 200-ps simulation. Alterations to the model include changes in the intraloop, main-chain hydrogen bonding network of loop H3, and adjustments of Tyr and Lys side chains of H3 induced by hydrogen bonding to water molecules. The structures observed during molecular dynamics support the conclusion of the previous paper that hydrogen bonding will play the dominant role in antibody-insulin recognition. Determination of the structure of the antibody by x-ray crystallography is currently being pursued to provide an experimental test of these results. The simulation appears to improve the model, but longer simulations at higher temperatures should be performed.     

Relativistic theoretical studies on hydrogen bonds and the electronic structure of aqueous solvated bis(uranyl) complex: an insight into explicit and/or implicit solvent effects

To understand the chemical behavior of uranyl complexes in water, a bis-uranyl [(phen)(UO₂)(μ₂–F)(F)]₂ (A; phen?=?phenanthroline, μ₂?=?doubly bridged) and its hydrated form A?·?(H₂O)_n (n?=?2, 4 and 6) were examined using scalar relativistic density functional theory. The addition of water caused the phen ligands to deviate slightly from the U₂(μ₂–F)₂ plane, and red-shifts the U–F-terminal and U?=?O stretching vibrations. Four types of hydrogen bonds are present in the optimized hydrated A?·?(H₂O)_n complexes; their energies were calculated to fall within the range 4.37–6.77 kcal mol^-1, comparable to the typical values of 5.0 kcal mol^-1 reported for hydrogen bonds. An aqueous environment simulated by explicit and/or implicit models lowers and re-arranges the orbitals of the bis-uranyl complex.

UV-spectroscopy,electronic structure and ozonolytic reactivity of sesquiterpenes: a theoretical study

Sesquiterpenes, one of the most important classes of biogenic volatile organic compounds, are potentially significant precursors to secondary organic aerosols (SOAs) in nature. The electronic structure of sesquiterpenes and their reactivity in the ozonolysis reaction were investigated by density functional theory. Results from the CIS calculations combined with an analysis of transition intensities show that the first peaks in the ultraviolet (UV) spectra for saturated and unsaturated isomers are σ–σ* and π–π* transitions, respectively. The UV absorption wavelength and absorbency are dictated by the electronic structures of these compounds. An increase in the number of double bonds and formation of a conjugated system expand the range of absorption in the UV region. An isomer with an endocyclic C = C bond presents weaker UV transition intensity than its corresponding exocyclic isomer. Results from conceptual DFT chemical reactivity indices of isomers suggest that no quantitative linear relationships between the structural changes and their reactivity, such as different degrees of unsaturated C = C double bonds, or the number of substituents attached to the C = C bond were discovered. In the ozonolysis reaction of sesquiterpenes, isomers with larger steric hindrance of substituents or endocyclic C = C bond possess higher chemical reactivity compared to isomers with smaller steric hindrandce or with an exocyclic C = C bond. These results are imperative to a better understanding of SOAs production mechanisms in the troposphere.     

Experimental and theoretical study on the structure and electronic spectra of imiquimod and its synthetic intermediates

Crystal structure of the imiquimod has been determined by single crystal X-ray analysis, imiquimod crystallizes in orthorhombic space group P2(1)2(1)2(1) and the molecules are linked along the c axis by the strong N-H ... N hydrogen bonds. A density functional theory (DFT) study on the electronic properties of imiquimod and its synthetic intermediates has been performed at B3LYP/6-31G* level, while taking solvent effects into account. Both the single configuration interaction (CIS) method and the time-dependent DFT (TDDFT) approaches have been used to calculate the electronic absorption spectra, and there is a good agreement between the calculated and experimental UV-visible absorption spectra. The fluorescence emission spectra of these three compounds in solution have also been measured, the relatively low fluorescence intensity is attributed to a chlorine-modulated heavy atom effect that enhances intersystem crossing between excited singlet and triplet states, and the relatively high fluorescence intensity of imiquimod results from an extended pi-conjugated system which enhances S(1)-->S(0) radiant transition.     

Hydrolysis of polynucleotides and the characterization of their secondary structure. A theoretical study

1. Single-stranded RNA may be regarded as an assembly of L hairpin loops each stabilized by N base pairs and each containing b unpaired residues; one loop is connected to another by c residues. 2. A theory based on the statistics of the random degradation of linear polymers was developed to relate N, b and c with the probability, p, of hydrolysing a diesterified phosphate bond. 3. The number of residues per hairpin loop, which is 2N+b, is related to the fraction, f, of the original loops remaining intact by the equation: 2N+b=logf/log(1–p). 4. The theory was extended to show that the number of residues per loop may be evaluated by fractionating the RNA after hydrolysis and examining the secondary structure of each fraction. Fragments that are shorter than the hairpin loop cannot reproduce the original secondary structure. The probability that a fragment will form an intact loop increases most rapidly for fragments of between 2N+b and 2(2N+b)+c residues. 5. The probability of producing a fragment capable of forming one, and only one, hairpin loop was related to N, b and c.     

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.     

A graph theoretical approach for predicting common RNA secondary structure motifs including pseudoknots in unaligned sequences

MOTIVATION: RNA structure motifs contained in mRNAs have been found to play important roles in regulating gene expression. However, identification of novel RNA regulatory motifs using computational methods has not been widely explored. Effective tools for predicting novel RNA regulatory motifs based on genomic sequences are needed. RESULTS: We present a new method for predicting common RNA secondary structure motifs in a set of functionally or evolutionarily related RNA sequences. This method is based on comparison of stems (palindromic helices) between sequences and is implemented by applying graph-theoretical approaches. It first finds all possible stable stems in each sequence and compares stems pairwise between sequences by some defined features to find stems conserved across any two sequences. Then by applying a maximum clique finding algorithm, it finds all significant stems conserved across at least k sequences. Finally, it assembles in topological order all possible compatible conserved stems shared by at least k sequences and reports a number of the best assembled stem sets as the best candidate common structure motifs. This method does not require prior structural alignment of the sequences and is able to detect pseudoknot structures. We have tested this approach on some RNA sequences with known secondary structures, in which it is capable of detecting the real structures completely or partially correctly and outperforms other existing programs for similar purposes. AVAILABILITY: The algorithm has been implemented in C++ in a program called comRNA, which is available at http://ural.wustl.edu/softwares.html     

A theoretical study of the effects of cyclic AMP phosphodiesterases during aggregation in Dictyostelium.

During aggregation the larger Dictyostelium species use cAMP as a chemoattractant and possibly also as a transmitter. In passage from cell to cell, cAMP levels are modulated by diffusion and by enzyme hydrolysis. It appears that the important cAMP-hydrolysing enzyme is a phosphodiesterase bound to the cell membrane, the main roles of which are (1) very fast hydrolysis of cAMP and (2) steepening of spatial cAMP gradients. An extracellular phosphodiesterase has no function, so far as can be conjectured from present data.     

Quantum-mechanical computations on the electronic structure of trans-resveratrol and trans-piceatannol: a theoretical study of the stacking interactions in trans-resveratrol dimers

Accurate quantum-chemical calculations based on the second-order M?ller-Plesset perturbation method (MP2) and density functional theory (DFT) were performed for the first time to investigate the electronic structures of trans-resveratrol and trans-piceatannol, as well as to study the stacking interaction between trans-resveratrol molecules. Ab initio MP2 calculations performed with using standard split-valence Pople basis sets led us to conclude that these compounds have structures that deviate strongly from planarity, whereas the DFT computations for the same basis sets revealed that the equilibrium geometries of these bioactive polyphenols are planar. Furthermore, the results obtained at the MP2(full)/aug-cc-pVTZ and B3LYP/aug-cc-pVTZ levels indicated that the geometries of trans-resveratrol and trans-piceatannol are practically planar at their absolute energy minima. The relative energies of the equilibrium geometries of trans-resveratrol on its potential energy surface were computed at the MP2(full)/aug-cc-pVTZ level. According to the results obtained, a T-shaped (edge-to-phase) conformer of trans-resveratrol dimer is the most stable in vacuum. This T-shaped conformer is mainly stabilized by strong hydrogen bonding and weak C-H...π interactions. Stacked structures with parallel-displaced trans-stilbene skeletons were also found to be energetically stable. The vertical separation and twist angle dependencies of the stacking energy were investigated at the MP2(full)/aug-cc-pVTZ, B3LYP/aug-cc-pVTZ, and HF/aug-cc-pVTZ levels. The standard B3LYP functional and the Hartree-Fock method neglect long-range attractive dispersion interactions. The MP2 computations revealed that the London dispersion energy cannot be neglected at long or short distances. The stacked model considered here may be useful for predicting the quantum nature of the interactions in π-stacked systems of other naturally occurring stilbenoids, and can help to enhance our understanding of the antioxidant and anticancer activities of trans-resveratrol.     

The mechanism of methanol decomposition by CuO. A theoretical study based on the reaction force and reaction electronic flux analysis

A theoretical study of methanol decomposition using a model representing the initial step of the reaction CH ₃ OH + CuO → CH ₂ O + H ₂ O + Cu is presented. Theoretical calculations using B3LYP/6-31 G along with Lanl2DZ pseudopotentials on metallic centers were performed and the results discussed within the framework of the reaction force analysis. It has been found that the reaction takes place following a stepwise mechanism: first, copper reduction (Cu ⁺² → Cu ⁺) accompanies the oxygen transposition and then a second reduction takes place (Cu ⁺ → Cu ⁰) together with a proton transfer that produce formaldehyde and release a water molecule.     

Molecular dynamics simulation study of the static and dynamic properties of a model colloidal suspension with explicit solvent

Molecular dynamics simulation was used to study a colloidal suspension with explicit solvent to determine how inclusion of the solvent affects the structure and dynamics of the system. The solute was modelled as a hard-core particle enclosed in a Weeks–Chandler–Andersen (WCA) potential shell, while the solvent was modelled as a simple WCA fluid. We found that when the solute–solvent interaction included a hard core equal to half of the solute hard-core diameter, large depletion effects arose, leading to an effective attraction and large deviations from hard-sphere structure for the colloidal component. It was found that these effects could be eliminated by reducing the hard-core distance parameter in the solute–solvent interaction, thus allowing the solvent to penetrate closer to the colloidal particles. Three different values for the solute–solvent hard-core parameter were systematically studied by comparing the static structure factor and radial distribution function to the predictions of the Percus–Yevick theory for hard spheres. When the optimal value of the solute–solvent hard-core interaction parameter was found, this model was then used to study the dynamical behaviour of the colloidal suspension. This was done by first measuring the velocity autocorrelation function (VACF) over a large range of packing fractions. We found that this model predicted the sign of the long-time tail in the VACF in agreement with experimental values, something that single component hard-sphere systems have failed to do. The intermediate scattering functions at low wavevector were briefly studied to determine their behaviour in a dilute system. It was found that they could be modelled using a simple diffusion equation with a wavevector independent diffusion coefficient, making this model an excellent analogue of experimentally studied hard-sphere colloids.     

Refined structure of alpha-lytic protease at 1.7 A resolution. Analysis of hydrogen bonding and solvent structure

The structure of alpha-lytic protease, a serine protease produced by the bacterium Lysobacter enzymogenes, has been refined at 1.7 A resolution. The conventional R-factor is 0.131 for the 14,996 reflections between 8 and 1.7 A resolution with I greater than or equal to 2 sigma (I). The model consists of 1391 protein atoms, two sulfate ions and 156 water molecules. The overall root-meansquare error is estimated to be about 0.14 A. The refined structure was compared with homologous enzymes alpha-chymotrypsin and Streptomyces griseus protease A and B. A new sequence numbering was derived based on the alignment of these structures. The comparison showed that the greatest structural homology is around the active site residues Asp102, His57 and Ser195, and that basic folding pathways are maintained despite chemical changes in the hydrophobic cores. The hydrogen bonds in the structure were tabulated and the distances and angles of interaction are similar to those found in small molecules. The analysis also revealed the presence of close intraresidue interactions. There are only a few direct intermolecular hydrogen bonds. Most intermolecular interactions involve bridging solvent molecules. The structural importance of hydrogen bonds involving the side-chain of Asx residues is discussed. All the negatively charged groups have a counterion nearby, while the excess positively charged groups are exposed to the solvent. One of the sulfate ions is located near the active site, whereas the other is close to the N terminus. Of the 156 water molecules, only seven are not involved in a hydrogen bond. Six of these have polar groups nearby, while the remaining one is in very weak density. There are nine internal water molecules, consisting of two monomers, two dimers and one trimer. No significant second shell of solvent is observed.     

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.     

Circular intensity differential scattering and chromatin-DNA structure. A combined theoretical approach

Circular intensity differential scattering (CIDS) has been proven a powerful method in determining the higher-order structure of large biopolymers, such as chromatin. Theoretical predictions of the expected differential light scattering of circularly polarized light have previously been made for chromatin, either within the Born approximation, treating nucleosomes as noninteracting, oblate ellipsoids, or within a multiple dipole approximation, treating nucleosomes as interacting spheres. In order to conduct a meaningful interpretation of the CIDS signal in terms of given geometric parameters of the chiral structure, we have in this paper combined the two approaches considering the mutual interactions of ellipsoidal nucleosomes. In the process we have also found a confirmation for the validity of the Born approximation itself.     

A theoretical and experimental investigation of the electronic spectra and tautomerization of nucleobases

The electronic structures of all possible tautomers of uracil, thymine, cytosine, adenine and guanine have been carefully examined within the MNDO-MO frame-work. Equilibrium geometries are determined and the relative stabilities are discussed. Allowance for solvent effect on the stabilities is made by assuming a tetrahedral solvent cage with the DNA base occupying its centre. The electronic absorption spectra of the studied DNA bases, in solvents of different polarities are recorded and discussed. Assignments of the observed bands are facilitated using MNDO-CI computations. It is suggested that in solution the DNA bases are in some statistical mixtures of the most stable tautomers, and the Watson-Crick (WC) structure cannot account for the observed spectra alone.     

A theoretical study of the reactive dimerization of HCN.

The reaction of two molecules of HCN to produce isomeric forms of (HCN)₂ has been studied theoretically through the use of CNDO/2 calculations together with a method of energy partitioning. The present work predicts that the most stable product of such a reaction is iminoacetonitrile, and that, of the mechanisms considered in the present work, the energetically most favourable, under isolated conditions, involves the dissociation of HCN to free radicals, followed by the reaction of the CN radical with an undissociated HCN molecule and the subsequent addition of hydrogen followed by rearrangement to the imine. However, the energetics are sufficiently similar that an ionic mechanism involving CN^? might be predicted for a condensed, base-catalyzed system.     

First-principles study of the structural transformation, electronic structure, and optical properties of crystalline 2,6-diamino-3,5-dinitropyrazine-1-oxide under high pressure

Periodic first-principles calculations have been performed to study the effect of high pressure on the geometric, electronic, and absorption properties of 2,6-diamino-3,5-dinitropyrazine-1-oxide (LLM-105) under hydrostatic pressures of 0–50 GPa. Obvious irregular changes in lattice constants, unit-cell angles, bond lengths, bond angles, and band gaps showed that crystalline LLM-105 undergoes four structural transformations at 8, 17, 25, and 42 GPa, respectively. The intramolecular H-bonds were strong at pressures of 0–41 GPa but weakened in the range 42–50 GPa. The lengths of the intermolecular H-bonds (<1.47 Å) indicated that these H-bonds have covalent character and tend to induce the formation of a new twelve-membered ring. Analysis of the DOS showed that the interactions between electrons, especially the valence electrons, strengthen under the influence of pressure. The p states play a very important role in chemical reactions of LLM-105. The absorption spectrum of LLM-105 displayed more bands—as well as stronger bands—in the fundamental absorption region when the pressure was high rather than low. A new absorption peak due to O–H stretching appeared at 18.3 eV above 40 GPa, indicating that covalent O–H bonds and a new twelve-membered ring are present in LLM-105.