Stationary points on the H2CO potential energy surface: dependence on theoretical level

A total of 36 stationary points have been located on the H₂CO potential energy surface by means of gradient extremal following. These 36 points are believed to represent all the important stationary points on this surface. There is no indication that the structure of the surface becomes less complicated as the size of the basis set is enlarged at the Hartree-Fock level of theory, but many of the second- and third-order saddle points disappear when electron correlation is introduced. Of the ten first-order saddle points (transition structures) located, the majority have reaction paths entering the associated minima in a side-on approach, i.e. these cannot be located by uphill walking from the minimum. Received: 5 February 1998 / Accepted: 21 May 1998 / Published online: 29 July 1998     

Bifurcation of reaction pathways: the set of valley ridge inflection points of a simple three-dimensional potential energy surface

This paper serves for the better understanding of the branching phenomenon of reaction paths of potential energy hypersurfaces in more than two dimensions. We apply the recently proposed reduced gradient following (RGF) method for the analysis of potential energy hypersurfaces having valley-ridge inflection (VRI) points. VRI points indicate the region of possible reaction path bifurcation. The relation between RGF and the so-called global Newton search for stationary points (Branin method) is shown. Using a 3D polynomial test surface, a whole 1D manifold of VRI points is obtained. Its relation to RGF curves, steepest descent and gradient extremals is discussed as well as the relation of the VRI manifold to bifurcation points of these curves. Received: 8 July 1998 / Accepted: 24 August 1998 / Published online: 23 November 1998     

Computation of stationary points via a homotopy method

A homotopy method is presented that locates both minimizers and saddle points of energy functions in an efficient manner. In contrast to other methods, it makes possible the exploration of large parts of potential energy surfaces. Along a homotopy path stationary points of odd and even order occur alternately. A path tracing procedure requiring only gradients and at most one evaluation of the Hessian matrix is given. Test results on a model potential and three MINDO/3 potentials are reported. Received: 6 May 1996 / Accepted: 2 April 1998 / Published online: 23 June 1998     

Dynamics of the transmembrane domain of the ErbB-2 receptor

The structure and dynamics of the ErbB-2 transmembrane domain have been examined using molecular dynamics techniques both in vacuum and within an explicit hydrated L-α-dilauroyl-phosphatidyl-ethanolamine environment. In-vacuum simulations show that a highly cooperative structural transition occurs frequently within the α-helical transmembrane domain which converts to local π-helices. We show that the α-helix alteration does not depend upon the force field or initial side-chain conformations but is intimately related to the sequence. The membrane-like environment does not prevent the structural transition in the helix but slows down the peptide dynamics indicating that the appearance of a π-bulge is not an artifact of the vacuum approximation. The consequences of π-helix formation could be very huge for the ErbB-2 receptor which is involved in numerous human cancers and also for other membrane proteins wherein similar local structures are also observed experimentally. Received: 9 May 1998 / Accepted: 3 September 1998 / Published online: 17 December 1998     

RISM-SCF study of the free-energy profile of the Menshutkin-type reaction NH3+CH3Cl→NH3CH3++Cl− in aqueous solution

The free-energy profile for the Menshutkin-type reaction NH₃ + CH₃Cl → NH₃CH₃ ⁺ + Cl⁻ in aqueous solution is studied using the RISM-SCF method. The effect of electron correlation on the free-energy profile is estimated by the RISM-MP2 method at the HF optimized geometries along the reaction coordinate. Solvation was found to have a large influence on the vibrational frequencies at the reactant, transition state and product; these vibrational frequencies are utilized to calculate the zero-point energy correction of the free-energy profile. The computed barrier height and reaction exothermicity are in reasonable agreement with those of experiment and previous calculations. The change of solvation structure along the reaction path is represented by radial distribution functions between solute-solvent atomic sites. The mechanisms of the reaction are discussed from the view points of solute electronic and solvation structures. Received: 26 June 1998/Accepted: 28 August 1998 / Published online: 2 November 1998     

The catalyzed hydrosilation reaction: substituent effects

Ab initio electronic structure calculations using MP2 wavefunctions have been used to investigate a reaction path for the hydrosilation reaction catalyzed by divalent titanium [modeled by TiH₂, TiCl₂, and Ti(C₅H₅)₂]. Optimized structures and energies are presented. All model reactions predict a barrierless reaction path compared to a barrier of 78 kcal/mol for the uncatalyzed reaction. Received: 11 August 1998 / Accepted: 3 September 1998 / Published online: 23 February 1999     

On the automatic restricted-step rational-function-optimization method

The rational function optimization algorithm is one of the widely used methods to search stationary points on surfaces. However, one of the drawbacks of this method is the step reduction procedure to deal with the overstepping problem. We present and comment on a method such that the step obtained from the solution of the rational function equations possesses the desired correct length. The analysis and discussion of the method is mainly centered on the location and optimization of transition states. Received: 18 June 1998 / Accepted: 17 September 1998 / Published online: 23 November 1998     

Complexes of ammonia with propane and cyclopropane: electrostatic guidelines for ab initio treatment

A model based on the molecular electrostatic potential (MESP) is employed for the investigation of structures and energies of complexes of ammonia with propane and cyclopropane. The electrostatic model geometries are employed as starting points for an ab initio investigation at the self-consistent field and second-order M?ller-Plesset (MP2) levels. The most stable structures of C₃H₆..NH₃ and C₃H₈..NH₃ complexes have the interaction energies of 10.07 kJ/mol and 8.15 kJ/mol, respectively, at the MP2/6-31G(d,p) level. The energy rank order of the structures is not altered with the use of the 6-31++G(d,p) basis set, and the basis␣set superposition error has little effect. The interaction energy decomposition analysis shows that the electrostatic component is dominant over the other ones. MESP topography thus seems to offer valuable hints for predicting the structures of weakly bonded complexes. Received: 8 July 1998 / Accepted: 4 August 1998 / Published online: 2 November 1998     

Inhibition Kinetics of Cabbage Butterfly (<Emphasis Type="Italic">Pieris rapae</Emphasis> L.) Larvae Phenoloxidase Activity by 3-Hydroxy-4-Methoxybenzaldehyde Thiosemicarbazone

Phenoloxidase (PO) is a key enzyme in insect development, responsible for catalyzing the hydroxylation of tyrosine into o-diphenols and the oxidation of o-diphenols into o-quinones. In the present study, the kinetic assay in air-saturated solutions and the kinetic behavior of PO from Pieris rapae (Lepidoptera) larvae in the oxidation of l-tyrosine (a monophenol) and l-DOPA (l-3, 4-dihydroxyphenylalanine) (a diphenol) was studied. The inhibitory effects of 3-hydroxy-4-methoxybenzaldehyde thiosemicarbazone (3-H-4-MBT) on the monophenolase and diphenolase activities of PO were also studied. The results show that 3-H-4-MBT can inhibit both the monophenolase and diphenolase activities of PO. The lag period of l-tyrosine oxidation catalyzed by the enzyme was obviously lengthened and the steady-state activities of the enzyme sharply decreased. The inhibitor was found to be noncompetitively reversible with a K _I (K _I = K _IS) of 0.30 μmol/L and an estimated IC₅₀ of 0.14 ± 0.02 μmol/L for monophenolase and 0.26 ± 0.04 μmol/L for diphenolase. In the time course of the oxidation of l-DOPA catalyzed by the enzyme in the presence of different concentrations of 3-H-4-MBT, the rate decreased with increasing time until a straight line was approached. The microscopic rate constants for the reaction of 3-H-4-MBT with the enzyme were determined.     

Neural networks to study invariant features of protein folding

Protein secondary structures result both from short-range and long-range interactions. Here neural networks are used to implement a procedure to detect regions of the protein backbone where local interactions have an overwhelming effect in determining the formation of stretches in α-helical conformation. Within the framework of a modular view of protein folding we have argued that these structures correspond to the initiation sites of folding. The hypothesis to be tested in this paper is that sequence identity beside ensuring similarity of the three-dimensional conformation also entails similar folding mechanisms. In particular, we compare the location and sequence variability of the initiation sites extracted from a set of proteins homologous to horse heart cytochrome c. We present evidence that the initiation sites conserve their position in the aligned sequences and exhibit a more reduced variability in the residue composition than the rest of the protein. Received: 24 April 1998 / Accepted: 4 August 1998 / Published online: 11 November 1998     

A theoretical study on the first ionic states of vinyl fluoride, vinyl chloride, trifluoroethylene, and trichloroethylene with an analysis of the vibrational structures of the photoelectron spectra

Ab initio calculations have been performed to study the molecular structures and the vibrational levels of the first ionic states of vinyl fluoride, vinyl chloride, trifluoroethylene, and trichloroethylene. The equilibrium molecular structures and vibrational modes of these states are presented. The theoretical ionization intensity curves including the vibrational structures are also presented and compared with the photoelectron spectra. Received: 11 September 1998 / Accepted: 13 October 1998 / Published online: 1 February 1999     

Analyzing patterns between regular secondary structures using short structural building blocks defined by a hidden Markov model

Hidden Markov models were used to identify recurrent short 3D structural building blocks (SSBBs) describing protein backbones. Polypeptide chains were broken down into successive short segments defined by their inter-alpha-carbon distances. Fitting the model to a database of nonredundant proteins identified 12 distinct SSBBs and described the preferred pathways by which SSBBs were assembled to form the 3D structure of the proteins. Protein backbones were labelled in terms of these SSBBs. The observed SSBB preferences for fragments located between regular secondary structures suggested that they depended more on the following regular structure than on the preceding one. Extraction of repeated series of SSBBs between regular secondary structures showed some structural specificity within different connection types. These results confirm that SSBBs can be used as building blocks for analyzing protein structures, and can yield new information on the structures of the coils flanking secondary structures. Received: 14 May 1998 / Accepted: 4 August 1998 / Published online: 16 November 1998     

Anticancer Properties of Highly Purified l-Asparaginase from Withania somnifera L. against Acute Lymphoblastic Leukemia

Withania somnifera L. has been traditionally used as a sedative and hypnotic. The present study was carried out for the purification, characterization, and in vitro cytotoxicity of l-asparaginase from W. somnifera L. l-Asparaginase was purified from the fruits of W. somnifera L. up to 95% through chromatography. The purified l-asparaginase was characterized by size exclusion chromatography, polyacrylamide gel electrophoresis (PAGE), and 2D PAGE. The antitumor and growth inhibition effect of the l-asparaginase was assessed using [3-(4, 5-dimethyl-thiazol-2yl)-2, 5-diphenyl-tetrazolium bromide] (MTT) colorimetric dye reduction method. The purified enzyme is a homodimer, with a molecular mass of 72 ± 0.5 kDa, and the pI value of the enzyme was around 5.1. This is the first report of the plant containing l-asparaginase with antitumor activity. Data obtained from the MTT assay showed a LD₅₀ value of 1.45 ± 0.05 IU/ml. W. somnifera L. proved to be an effective and a novel source of l-asparaginase. Furthermore, it shows a lot of similarity with bacterial l-asparaginases EC-2.     

DFT calculations of the intermediate and transition state in the oxidation of NO by oxygen in the gas phase

The B3LYP density functional method using the extended basis set 6-311++G(3df) was used to calculate the stationary points along the reaction coordinate 2NO + O₂ → 2NO₂. The results of the calculation were compared with the reported physicochemical characteristics of this reaction. The origin of the barrierless activation of the oxygen molecule and driving force for the spontaneous oxidation of NO were examined.     

Transition state structure invariance to model system size and calculation levels: a QM/MM study of the carboxylation step catalyzed by Rubisco

The present study elucidates structural features related to the molecular mechanism in the carboxylation step of the reaction catalyzed by Rubisco. Starting from the initial X-ray Protein Data Bank structure of a Rubisco monomer, the reactive subsystem in vacuo is subjected to quantum chemical semiempirical and ab initio studies, while the effects of the protein environments are included by means of a hybrid quantum mechanical/molecular mechanical (QM/MM) approach. The QM/MM is used to characterize the transition structure for carboxylation inside the protein. The calculations were made with the AM1/CHARMM/GRACE scheme. Comparisons between the in vacuo and in situ transition structures show remarkable invariance with respect to geometric parameters, index and transition vector amplitudes. The transition state couples the carbon dioxide attack to the C2 center of the substrate in its dienol form with a simultaneous intramolecular hydrogen transfer from the C2 atom to the hydroxyl group linked to the C3 center. This study suggests that carboxylation may be simultaneously coupled to the activation of the C3 center in the enzyme. Received: 24 March 1998 / Accepted: 3 September 1998 / Published online: 10 December 1998     

Structure effects on isomerization pathways and vibrational spectra of epoxysaccharides: a numerical study

Results of a comparative analysis of conformational possibilities of the hexopyranose ring of six epoxysaccharides differing from each other by the position of the oxirane ring within the limits of the hexapyranose ring and having different orientations of substituents and different positions of the oxirane ring with respect to the skeleton plane of the molecules are presented. Numerical simulations based on the Wiberg and Boyd method made it possible to determine all the stationary forms in which anhydropyranose rings can exist. The effect of various structural factors on the character of conformational transformations, heights of transition barriers, and the energy of stationary forms has been investigated. Normal vibrational modes of the stationary forms of the compounds were calculated using molecular mechanics. Based on results of our simulations, we predict a strong effect of steric factors on the vibrational spectra of sugar epoxides. Received: 24 March 1998 / Accepted: 3 September 1998 / Published online: 17 December 1998     

Poisson-Boltzmann calculations versus molecular dynamics simulations for calculating the electrostatic potential of a solvated peptide

We performed a very long molecular dynamics simulation of a peptide in explicit water molecules and ions and averaged the electrostatic potential caused by peptide, water and ions at eight points in the vicinity of the peptide. These electrostatic potential values were directly compared to the potential calculated by solving the non-linear Poisson-Boltzmann equation for the system, which describes the solvent using continuum electrostatics. We analyze the contribution of dielectric constant, conformational flexibility and solvation effects on the electrostatic potential at these eight points. Received: 24 April 1998 / Accepted: 4 August 1998 / Published online: 23 November 1998     

Molecular modeling study of an abasic DNA undecamer duplex: d(GCGTGOGTGCG) · d(CGCACTCACGC)

Molecular mechanics calculations were performed with the JUMNA program on d(GCGTGOGTGCG) · d(CGCACTCACGC) where “O” is a modified abasic site: 3-hydroxy-2-(hydroxymethyl)tetrahydrofuran. From energy minimizations, for intrahelical or extrahelical positions of the unpaired thymine, various structures with different curvatures were obtained. Dynamical properties of this abasic sequence were also investigated through the controlled studies of DNA bending. Poisson-Boltzmann calculations were used to mimic the electrostatic effect of solvent on this sequence. The lowest energy structures show an acceptable agreement with experimental data. Received: 1 June 1998 / Accepted: 17 September 1998 / Published online: 10 December 1998     

Recent advances in molecular dynamics simulation towards the realistic representation of biomolecules in solution

Coupled advances in empirical force fields and classical molecular dynamics simulation methodologies, combined with the availability of faster computers, has lead to significant progress towards accurately representing the structure and dynamics of biomolecular systems, such as proteins, nucleic acids, and lipids in their native environments. Thanks to these advances, simulation results are moving beyond merely evaluating force fields, displaying expected structural fluctuations, or demonstrating low root-mean-squared deviations from experimental structures and now provide believable structural insight into a variety of processes such as the stabilization of A-DNA in mixed water and ethanol solution or reversible β-peptide folding in methanol. The purpose of this overview is to take stock of these recent advances in biomolecular simulation and point out some common deficiencies exposed in longer simulations. The most significant methodological advances relate to the development of fast methods to properly treat long-range electrostatic interactions, and in this regard the fast Ewald methods are becoming the de facto standard. Received: 9 April 1998 / Accepted: 21 May 1998 / Published online: 13 August 1998     

Electron affinities, excitation energies and ionization potentials of the transition metals (I) Sc and Ti

The electron affinities of the Sc and Ti atoms have been obtained by configuration interaction calculations. Energy convergence with respect to the systematic expansion of both the one-electron basis set and the configuration space was investigated for valence electrons, and the inclusion of correlation contributions from core electrons and relativistic effects gave the electron affinities of 0.181 eV and 0.163 eV for Sc and Ti, respectively. These are in excellent agreement with the observed values of 0.189 ± 0.020 eV and 0.080 eV. The same approach was applied for the first excited states and positive ions of both atoms. Excellent agreement with the experimental results was also obtained for these states. Received: 16 February 1998 / Accepted: 2 April 1998 / Published online: 23 June 1998