An ab initio study of the guanidinium groups in saxitoxin

Quantum chemical (Hartree-Fock) calculations were performed on neutral and protonated saxitoxin in order to obtain optimum geometries, rotational energy barriers for the guanidinium ions and proton affinities. For comparison purposes, as model compounds, guanidinium systems in five and six membered rings were also investigated. In addition, DFT (B3LYP) calculations with the 6-31G** basis set were performed and the sodium affinities of the guanidinium groups in saxitoxin were obtained. It was concluded that the inhibition of the sodium channels by the saxitoxin is due to the interaction of the guanidinium group with carboxylate groups from the wall of the channel and not to the binding of the sodium ions. Figure Calculated structure of Compound 1, neutral saxitoxin. a Calculated structure of Compound 1a, saxitoxin protonated on the guanidine of the five-membered ring. b Calculated structure of Compound 1b, saxitoxin protonated on the guanidine of the six-membered ring     

An ab initio Linear-Scaling Schem

Abstract

In this paper we briefly survey the current state of ab initio calculations in terms of the accuracy and range of applicability of these methods for studying complex processes in real materials. We highlight some of the successes and limitations of these techniques and discuss the extent to which linear-scaling methods are able to extend the scope and scale of ab initio calculations. We argue that a combination of linear-scaling methods and hybrid modelling schemes is required to overcome many of the difficulties currently faced by conventional schemes, and present our own contributions towards the development of a robust and reliable linear-scaling method.     

An ab initio molecular orbital study on the characteristics of 8-hydroxyguanine

To investigate the mechanism by which the 8-hydroxyguanine residue in DNA affects the fidelity of DNA replication, the intrinsic properties of this modified base were investigated using an ab initio molecular orbital method. The most stable 8-hydroxyguanine form was revealed to be 6,8-diketo. The addition of an oxygen atom to the 8 position of a guanine base was shown to change the electrostatic potential of the molecule entirely and to give it a negative character. This effect may influence the local structure of 8-hydroxyguanine-containing DNA and the interaction with DNA polymerase, thereby resulting in infidelity of DNA replication.     

Valence isomerization of 2-phospha-4-silabicyclo[1.1.0]butane: a high-level ab initio study

The rearrangements for 2-phospha-4-silabicyclo[1.1.0]butane, analogous to the valence isomerization of the hydrocarbons bicyclobutane, 1,3-butadiene, and cyclobutene, were studied at the (U)QCISD(T)/6-311+G**//(U)QCISD/6-31G* level of theory. The monocyclic 1,2-dihydro-1,2-phosphasiletes are shown to be the thermodynamically preferred product, in contrast to the isomerization of the hydrocarbons, which favors the 1,3-butadiene structure. Furthermore, an unprecedented direct isomerization pathway to the 1,2-dihydro-1,2-phosphasiletes was identified. This pathway is competitive with the isomerization via the open-chain butadienes and becomes favorable when electron-donating substituents are present on silicon. Figure 2-Phospha-4-silabicyclo[1.1.0]butane can isomerize directly into the more stable P,Si-cyclobutene via an unprecedented [sigma2s+sigma2a] process, which becomes favorable over the isomerization via the P,Si-butadiene when electron-donating substituents are present on silicon.     

Indigo stability: an ab initio study

This work shows that indigo's high stability can be attributed both to the large π conjugation inside the molecule and to intra- and intermolecular hydrogen bonds. The theoretical investigation of indigo's electronic structure has been performed using high-level methods. To understand the interactions in solid state, calculations of the dimer system with both molecules in the same plane was carried out. In the monomer, two intramolecular hydrogen bridges between amino and carbonyl groups occupy positions that would otherwise be the most reactive ones for nucleophilic and electrophilic attacks. In the dimer, amino and carbonyl groups on different monomers form intermolecular multicentred non-linear hydrogen bonds in six-member rings, protecting again the same reactive centres and explaining the limited solubility of indigo. The addition of the free radical OH breaks the central C = C double bond, the conjugation and the hydrogen bridges as a first step. The Gibbs energy calculation favours the addition of OH radical over C1.     

An ab initio computational study of thiamin synthesis from gaseous reactants of the interstellar medium

A set of chemical reactions is proposed to account for the formation of thiamin derivatives from gaseous reactants that have been identified in the interstellar medium, and may have been relevant to a prebiotic atmosphere. The gaseous mixture consisted of methanimine, acetonitrile, cyanoacetylene, ammonia, acetylene, allylene, hydrogen sulfide, thioformaldehyde, and hydrogen in the presence of water. Most of the reactions appear to be exothermic. The reactions have been shown to be feasible from the overall enthalpy changes in the ZKE approximation at the HF and MP2/6-31G(*) level.     

Cooperative effects in α-helices: An ab initio molecular-orbital study

Some properties of α-helices of polyclycine and polyalanine, up to the decapeptide, were investigated by ab initio molecular-orbital calculations. These helices were found to be unstable relative to the corresponding “fully extended chain” conformation. The electric field of helices of 8–10 residues is about 20% stronger than that of models built from noninteracting monomers, for example. This is a result of cooperativity, which is essentially governed by the intramolecular hydrogen bonds. The cooperativity is manifest in all properties of the helices: relative stability, dipole moment, proton affinity, electrical potential. The electric potential of helices of three and four residues is such that their instability can be compensated for by a single charged group acting as an “initiator.” The computed proton affinity of the (Ala)₈ α-helix is about 45 kcal/mol larger than that of formamide, which confirms that long helices may be protonated at the carboxyl end in solution.     

UV photoelectron spectroscopy and ab initio characterization of valence orbital structures and conformations of neutral phosphate esters

The HeI UV photoelectron spectrum of trimethyl phosphate (TMP) has been measured and interpreted with the aid of SCF molecular orbital calculations carried out with STO-3G, STO-3G* and 4-31G basis functions. The photoelectron spectrum of TMP is more accurately reproduced by results from 4-31G calculations than by results from STO-3G or STO-3G* calculations. However, all three basis sets yield results which predict the same assignment of the photoelectron spectrum. Results at the 4-31G level indicate that whether calculations are based on crystallographic bond angles and bond lengths or on STO-3G optimized geometries has little effect on the energetic ordering of the upper occupied orbitals. The energetic ordering of orbitals is also found to be only weakly dependent upon the torsional angle phi, describing rotation of ester groups about P-O bonds and upon the torsional angle psi, describing rotation of methyl groups about C-O bonds. For trimethyl phosphate, with C3 symmetry, the vertical ionization potentials of the upper occupied orbitals are 10.81 eV (8e), 11.4 eV (9a), 11.93 eV (7e), 12.6-12.9 eV (8a and 6e), 14.4 eV (7a) and 15.0-16.0 eV (5e and 6a). Calculations at the 4-31G level indicate that many of the highest occupied orbitals in neutral dimethyl phosphate and methyl phosphate have energies and electron distributions similar to orbitals in TMP. For TMP, a search for optimized values of phi and psi has been carried out at the STO-3G*level. In agreement with previous NMR studies and with classical potential calculations, the STO-3G* results indicate that both the gauche (phi = 53.1 degrees) and anticlinal (phi = 141.9 degrees) conformations are thermally accessible. Also in agreement with the classical potential calculations, the STO-3G* results predict that in the all gauche conformation energy is minimized when the methyl groups assume a staggered geometry (psi = 60 degrees to 80 degrees) and that an energy maximum occurs for an eclipsed geometry (phi = 0 degrees to 20 degrees). A study of the dependence of optimized values of O-P-O ester bond angles on the torsional angles, phi, was carried out at the STO-3G, STO-3G* and 4-31G levels. The results demonstrate that for C3 symmetry, the coupling of O-P-O angles to phi is influence by repulsive steric interactions.     

An explanation of the induction of mutations by 2-aminopurine from an ab initio molecular orbital study

The molecular mechanism of induction of mutations by 2-aminopurine (AP) was studied by an ab initio molecular orbital method. Cytosine (C) is converted to its disfavored imino tautomer more easily than AP, judging from the calculated total energies of the bases and the base analogue. This suggests that a stable AP:C base mispair via two hydrogen bonds can be formed with the imino tautomer of C. These results stress the importance of the imino form of C in AP-induced mutagenesis and support the 'trigger mechanism', in which formation of one hydrogen bond between AP and C is considered to stimulate the tautomeric shift of AP or C. The calculated relative stabilities of various base pairs and mispairs were in good agreement with experimental findings.     

Serine proteases: an ab initio molecular dynamics study

In serine proteases (SPs), the H-bond between His57 and Asp102 and that between Gly193 and the transition state intermediate play a crucial role in enzymatic function. To shed light on the nature of these interactions, we have carried out ab initio molecular dynamics simulations on complexes representing adducts between the reaction intermediate and elastase (one protein belonging to the SP family). Our calculations indicate the presence of a low-barrier H-bond between His57 and Asp102, in complete agreement with NMR experiments on enzyme-transition state analogue complexes. Comparison with an ab initio molecular dynamics simulation on a model of the substrate-enzyme adduct indicates that the Gly193-induced strong stabilization of the intermediate is accomplished by charge/dipole interactions and not by H-bonding as previously suggested. Inclusion of the protein electric field in the calculations does not affect significantly the charge distribution.     

Benchmarking of TASSER in the ab initio limit

A significant number of protein sequences in a given proteome have no obvious evolutionarily related protein in the database of solved protein structures, the PDB. Under these conditions, ab initio or template-free modeling methods are the sole means of predicting protein structure. To assess its expected performance on proteomes, the TASSER structure prediction algorithm is benchmarked in the ab initio limit on a representative set of 1129 nonhomologous sequences ranging from 40 to 200 residues that cover the PDB at 30% sequence identity and which adopt alpha, alpha + beta, and beta secondary structures. For sequences in the 40-100 (100-200) residue range, as assessed by their root mean square deviation from native, RMSD, the best of the top five ranked models of TASSER has a global fold that is significantly close to the native structure for 25% (16%) of the sequences, and with a correct identification of the structure of the protein core for 59% (36%). In the absence of a native structure, the structural similarity among the top five ranked models is a moderately reliable predictor of folding accuracy. If we classify the sequences according to their secondary structure content, then 64% (36%) of alpha, 43% (24%) of alpha + beta, and 20% (12%) of beta sequences in the 40-100 (100-200) residue range have a significant TM-score (TM-score > or = 0.4). TASSER performs best on helical proteins because there are less secondary structural elements to arrange in a helical protein than in a beta protein of equal length, since the average length of a helix is longer than that of a strand. In addition, helical proteins have shorter loops and dangling tails. If we exclude these flexible fragments, then TASSER has similar accuracy for sequences containing the same number of secondary structural elements, irrespective of whether they are helices and/or strands. Thus, it is the effective configurational entropy of the protein that dictates the average likelihood of correctly arranging the secondary structure elements.     

Structural phase transition of CdTe: an ab initio study

A constant pressure ab initio MD technique and density functional theory with a generalized gradient approximation (GGA) was used to study the pressure-induced phase transition in zinc-blende CdTe. We found that CdTe undergoes a structural first-order phase transition to $ {\text{I}}\overline 4 {\text{m2}} $ (binary β-tin) tetragonal structure in the constant pressure molecular dynamics simulation at 20 GPa. When the pressure was increased to 50 GPa, the phase of tetragonal structure converted to a new Imm2 orthorhombic structure. These phase transformations were also calculated by using the enthalpy calculations. Transition phases, lattice parameters and bulk properties we attained are comparable with experimental and theoretical data.     

Pressure-induced phase transition in wurtzite ZnTe: an ab initio study

A constant pressure ab initio MD technique and density functional theory with a generalized gradient approximation (GGA) was used to study the pressure-induced phase transition in wurtzite ZnTe. A first-order phase transition from the wurtzite structure to a Cmcm structure was successfully observed in a constant-pressure molecular dynamics simulation. This phase transformation was also analyzed using enthalpy calculations. We also investigated the stability of wurtzite (WZ) and zinc-blende (ZB) phases from energy–volume calculations, and found that both structures show quite similar equations of state and transform into a Cmcm structure at 16 GPa using enthalpy calculations, in agreement with experimental observations. The transition phase, lattice parameters and bulk properties we obtained are comparable with experimental and theoretical data.     

An ab initio study of the formation of alkoxy radicals by reactions of simple alkenes with the OH radical

The formation of ethoxy, propoxy and butoxy radicals in the reactions of ethene, propene, cis- and trans-2-butene with the OH radical has been modeled in the gaseous phase at the MP2/6-31+G(d) level. All the possible reaction pathways have been investigated, and the structures as well as the energetics have been determined. The reactants, prereaction complexes, transition states and products located along the alkene-OH radical reaction coordinates have been discussed thoroughly. The rate determining step for these reactions is the conversion of hydroxyalkyl radicals to alkoxy radicals. The reaction barriers and exothermicities for these small alkenes are more or less identical for the compounds studied. Nevertheless, addition of OH to the central carbon atom of propene is slightly favored kinetically and thermodynamically (1 kcal mol^-1) over the others.     

Conformational flexibility of the catalytic Asp dyad in HIV-1 protease: An ab initio study on the free enzyme

The enzyme protease from the human immunodeficiency virus type 1 (HIV-1 PR) is one of the main targets for therapeutic intervention in AIDS. Computer modeling is useful for probing the binding of novel ligands, yet empirical force field-based methods have encountered problems in adequately describing interactions of the catalytic aspartyl pair. In this work we use ab initio dynamic methods to study the molecular interactions and the conformational flexibility of the Asp dyad in the free enzyme. Calculations are performed on model complexes that include, besides the Asp dyad, the conserved Thr26 and Gly27 residues and water molecules present in the active site channel. Our calculations provide proton location and binding mode of the active-site water molecule, which turn out to be different from those of the eukariotic isoenzyme. Furthermore, the calculations reproduce well the structural features of the aspartyl dyad in the protein. Finally, they allow the identification of both dipole/charge interactions and a low-barrier hydrogen bond as important stabilizing factors for the peculiar conformation of the active site. These findings are consistent with site-directed mutagenesis experiments on the 27, 27; positions (Bagossi et al., Protein Eng 1996;9:997-1003). The electric field of the protein frame (included in some of the calculations) does not affect significantly the chemical bonding at the cleavage site. Proteins 2000;39:26-36.     

蛋白质结构从头预测方法研究进展

蛋白质结构从头预测是不依赖模板仅从氨基酸序列信息得到天然结构。它的关键是正确定义能量函数、精确选用计算机搜索算法来寻找能量最低值。基于此,本文系统介绍了能量函数和构象搜索策略,并列举了几种比较成功的从头预测方法,通过比较得出结论:基于统计学知识的能量函数是近年来从头预测发展的主要方向,现有从头预测的构象搜索都用到Monte Carlo法。这表明随着蛋白质结构预测研究的深入,能量函数的构建、构象搜索方法的选择、大分子蛋白质结构的从头预测等关键性问题都取得了突破性进展。     

Structural phase transition of BeTe: an ab initio molecular dynamics study

Beryllium telluride (BeTe) with cubic zinc-blende (ZB) structure was studied using ab initio constant pressure method under high pressure. The ab initio molecular dynamics (MD) approach for constant pressure was studied and it was found that the first order phase transition occurs from the ZB structure to the nickel arsenide (NiAs) structure. It has been shown that the MD simulation predicts the transition pressure P _T more than the value obtained by the static enthalpy and experimental data. The structural pathway reveals MD simulation such as cubic → tetragonal → orthorhombic → monoclinic → orthorhombic → hexagonal, leading the ZB to NiAs phase. The phase transformation is accompanied by a 10% volume drop and at 80 GPa is likely to be around 35 GPa in the experiment. In the present study, our obtained values can be compared with the experimental and theoretical results.

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Graphical abstract The energy-volume relation and ZB phase for the BeTe