Gas phase and water solution conformational analysis of the herbicide diuron (DCMU): an ab initio study

In the present work, the conformational equilibrium for the herbicide diuron (DCMU) has been investigated using high level ab initio calculations. The solvent effect was included through two different continuum models: (1) the real cavity IPCM method and (2) the standard dipole Onsager model SCRF. The effect due to solute-solvent hydrogen-bond interactions was analyzed considering a hybrid discreet-continuum model. At the Hartree-Fock level, the gas phase results showed that only the trans forms (A and B) are present in the equilibrium mixture, with the relative concentrations found to be 33% (A) and 67% (B) (HF/6-311+G**//6-31G**). When the electronic correlation effect is included (MP2/6-31G*//HF/6-31G*), a relative stabilization of the cis forms was observed, with the conformational distribution calculated as 38% (A), 50% (B), 6% (C) and 6% (D). The trans conformations were found to be completely planar, which has been considered to be a prerequisite for the herbicide binding. In water solution, the trans conformation A should be the most abundant conformer, the IPCM and SCRF values being ca. 100% and ca. 85% respectively. The IPCM calculations with the isodensity level set to 0.0005 present a conformational distribution close to that obtained from the hybrid model [92% (A) and 8% (B)], which has been considered our best solvent approach. Regarding the biological action of urea-type herbicides, the results presented here are important, because some QSAR studies have suggested that the partition coefficient is related to the herbicide activity, so the conformational equilibrium may play a role in the biological action. Received: 23 February 1998 / Accepted: 28 May 1998 / Published online: 19 August 1998     

Conformational free energy surface of the linear DPDPE peptide: cost of pre-organization for disulfide bond formation

We have calculated the free energy differences between four conformers of the linear form of the opioid pentapeptide DPDPE in aqueous solution. The conformers are Cyc, representing the structure adopted by the linear peptide prior to disulfide bond formation, β _C and β _E , two slightly different β-turns previously identified in unconstrained molecular dynamics simulations, and Ext, an extended structure. Our simulations indicate that β _E is the most stable of the studied conformers of linear DPDPE in aqueous solution, with β _C , Cyc and Ext having free energies higher by 2.3, 6.3, and 28.2 kcal/mol, respectively. The free energy differences of 4.0 kcal/mol between β _C and Cyc, and 6.3 kcal/mol between β _E and Cyc, reflect the cost of pre-organizing the linear peptide into a conformation conducive for disulfide bond formation. Such a conformational change is a pre-requisite for the chemical reaction of S–S bond formation to proceed. The relatively low population of the cyclic-like structure agrees qualitatively with observed lower potency and different receptor specificity of the linear form relative to the cyclic peptide, and with previous unconstrained simulation results. Free energy component analysis indicates that the moderate stability difference of 4.0–6.3 kcal/mol between the β-turns and the cyclic-like structure results from cancellation of two large opposing effects. In accord with intuition, the relaxed β-turns have conformational strain 43–45 kcal/mol lower than the Cyc structure. However, the cyclic-like conformer interacts with water about 39 kcal/mol strongly than the open β-turns. Our simulations are the first application of the recently developed multidimensional conformational free energy thermodynamic integration (CFTI) protocol to a solvated system, with fast convergence of the free energy obtained by fixing all flexible dihedrals. Additionally, the availability of the CFTI multidimensional free energy gradient leads to a new decomposition scheme, giving the contribution of each fixed dihedral to the overall free energy change and providing additional insight into the microscopic mechanisms of the studied processes. Received: 20 April 1998 / Accepted: 9 September 1998 / Published online: 7 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     

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     

Periodic orbits and vibrational wave functions for DCP: nonlinear resonances in isotopically substituted molecules

We investigate, by means of classical and quantum mechanics, how isotopic substitution (H/D) affects the vibrational dynamics of HCP. The analysis of periodic orbits, including the location of the principal families as well as saddle node bifurcations, reveals a totally different picture for the phase-space resonance structure for HCP and DCP. While HCP is characterized by a 1:2 resonance between the CP stretch and the bending mode, DCP shows a 1:2 resonance between the two stretching degrees of freedom. Saddle node bifurcations, which are associated with large-amplitude motion of H/D moving from the C- to the P-end, appear at considerably higher energies in DCP than in HCP. These results are in accord with exact quantum mechanical calculations of the vibrational levels. Received: 24 June 1998 / Accepted: 10 August 1998 / Published online: 9 October 1998     

Examining ligand-protein interactions with binding-energy landscapes

Binding-energy landscapes are used to investigate the thermodynamics of molecular recognition for the pteridine ring, a recognition anchor in binding with dihydrofolate reductase, and two molecules with the same shape but different heteroatom substitutions. The relative importance of hydrogen bonding and hydrophobic interactions in this system is analyzed by comparing these three different decorations of the pteridine scaffold. Received: 5 May 1998 / Accepted: 3 September 1998 / Published online: 17 December 1998     

Argon-matrix-isolation Raman spectra and density functional study of 1,3-butadiene conformers

s-trans, s-cis and gauche conformers of 1,3-butadiene have been studied using density functional theory and the coupled-cluster method using double substitutions (CCD). Matrix isolation Raman and IR data for the minor conformer were obtained and are used in combination with the theoretical results to resolve earlier ambiguities in vibrational assignments. Based on high-quality Hessians, new harmonic stretching force constants are reported for the carbon backbone of s-trans-1,3-butadiene. For the minor conformer the best unscaled root mean square error of the calculated frequencies for the s-cis and gauche geometries are 17.5 cm⁻¹ and 7.4 cm⁻¹, respectively, primarily due to a better agreement of the gauche results for the vibrations at 983 cm⁻¹, 596 cm⁻¹ and 470 cm⁻¹ which depend strongly on the torsional angle. Although this points towards the gauche form rather than the s-cis form, the calculated transition dipole moment directions at the CCD/6-311G(d,p) level confirm the earlier conclusion that the minor conformer has C _{2 v} symmetry in the matrix. It is concluded that either the better agreement between the frequencies calculated for the gauche form and the observed values is coincidental, or that the molecule is indeed nonplanar in the matrix and tunnels very rapidly between the two mirror-image forms (or its lowest vibrational level lies above the barrier). Received: 1 July 1998 / Accepted: 26 October 1998 / Published online: 15 February 1999     

Theoretical study on the lowest-frequency mode of the flavin ring

The dynamic aspects along the normal vibrational motions of the lowest frequencies in the oxidized, radical, and reduced states of flavin (isoalloxazine) have been studied. In comparison with the twist motions in the oxidized state, the butterfly motions in the radical and reduced states turned out to bring more significant variations to the frontier molecular orbital energies and to the charge distributions on the atoms of the pyrazine ring in isoalloxazine. It can be considered that the electron transfers from and to the isoalloxazine ring can be adjusted or controlled by these variations. In the reduced states the electron release from the molecule, and in the radical states the electron release from or acceptance by the molecule, could be impelled by the butterfly motions, while in the oxidized state the electron acceptance by the molecule could be accelerated slightly by the twist motion. Received: 30 September 1998 / Accepted: 20 January 1999 / Published online: 7 June 1999     

Theoretical studies of the potential energy surface and wavepacket dynamics of the Li3 system

The three-dimensional (3D) potential energy surface of the ground state of Li₃ was determined by the multireference configuration interaction method. The vibrational motions and pseudorotation were investigated by a 3D time-dependent wavepacket formalism. The analytical expression of the 3D surface is given and the results of vibrational analyses at several critical points are presented. The low-lying excited states of Li₃ were examined for the C _{2 v} structure and the vertical and adiabatic excitation energies were calculated. The ground and singlet excited states of Li₂ were calculated and their spectroscopic constants compare well with the experimental values. A 3D wavepacket calculation was performed for simulations of the stimulated emission pumping spectrum in which the A state was taken as an intermediate. The recurrences of the autocorrelation functions were characterized by classical trajectory calculations. The autocorrelation functions obtained by wavepacket propagation are reproduced well by the accumulation of the classical trajectories in the short-time region. Received: 2 July 1998 / Accepted: 3 September 1998 / Published online: 8 February 1999     

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     

Study of flexible joints and permanent bends in DNA fragments by brownian dynamics simulations

The use of Brownian dynamics simulations to investigate the presence of structural (kinks) and dynamic (bulges) anomalies in short DNA stretches is analyzed in connection with a string-of-beads model. A scaling method to choose the hydrodynamic translational and rotational parameters of the beads is proposed and tested on straight, kinked and bulged DNA fragments 17 nm long. The model reproduces the rigid-body rotational diffusion for the straight DNA and for the fluorescence polarization anisotropy decay of the kinked and bulged DNAs the model predicts a different behavior which is found experimentally. Received: 24 March 1998 / Accepted: 3 September 1998 / Published online: 23 November 1998     

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     

Transition-state structures for describing the enzyme-catalyzed mechanisms of rubisco

The carboxylation and oxygenation processes of a model substrate, 3,4-dihydroxy-2-pentanone, have been theoreticaly characterized as a set of steps, mimicking the corresponding reactions of D-ribulose-1,5-bisphosphate catalyzed by rubisco. A theoretical characterization is carried out of transition-state structures and possible molecular intermediates represented as saddle points of index 1 and minimum energy structures, respectively. The quantum chemical characterization, at the HF/3-21G calculation level, of these stationary points is used to rationalize and to discuss both catalyzed sequences. The reported set of these stationary points maps out most experimental aspects of the reaction pathways for the real system. Received: 24 March 1998 / Accepted: 3 September 1998 / Published online: 10 December 1998     

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     

Peptides in membranes: assessment of environmental effects via simulations using an implicit solvation model

A recently developed implicit solvation model is applied to Monte Carlo simulations of peptides in bilayer-mimetic and polar environments. The model employs the formalism of atomic solvation parameters and reproduces experimental data. Solvent effects on the␣structure of the following peptides were studied: 20-residue poly-Leu and poly-Val, transmembrane helix A of bacteriorhodopsin, magainin2. It was shown that a␣membrane-like environment considerably promotes α-helix formation (all the peptides were found to be α-helical), while simulations in water reveal helix distortion. Consistency of the results with experimental data and further implications of the model are discussed. Received: 24 April 1998 / Accepted: 3 September 1998 / Published online: 10 December 1998     

Information about the biologically relevant properties of Clostridium pasteurianum rubredoxin obtained from modeling and dynamics simulations of molecular variants

Rubredoxins are small electron transfer proteins containing one iron atom at their active site. The rubredoxin from the anaerobic bacterium Clostridium pasteurianum has been subjected to molecular dynamics studies starting from the minimized solvated structure. The results of the simulations have been compared with identical ones carried out with selected mutated forms of the protein obtained by molecular modeling. Surface residues, which are highly conserved among rubredoxins and close to the cysteine ligands, can be replaced by glutamates, i.e. long chain carboxylates. The main structural consequence is a shift of the protein backbone bearing conserved aromatic residues. Reciprocally, substitution of the aromatic residue closest to the iron atom shifts the cysteine-containing peptide fragments. These observations have been related to the changes in electron transfer and redox properties previously measured for this set of rubredoxin molecular variants. Received: 16 May 1998 / Accepted: 4 August 1998 / Published online: 2 November 1998     

Vibrational and correlation effects on properties of water

Large basis set, ab initio potential energy and property surfaces of water have been used with quantum Monte Carlo vibrational analysis in the evaluation of the molecule's rotational constants, zero-point energy, and dipole moment. While there are clearly differences in vibrational state parameters due to including correlation effects, the vibrational averaging effect on rotational constants is very nearly additive with the correlation effect. This has implications for evaluation and estimation of properties of molecules in specific vibrational states. Received: 9 February 1999 / Accepted: 11 February 1999 / Published online: 5 May 1999     

Prediction of protein structure using a knowledge-based off-lattice united-residue force field and global optimization methods

A united-residue model of polypeptide chains developed in our laboratories with united side-chains and united peptide groups as interaction sites is presented. The model is designed to work in continuous space; hence efficient global-optimization methods can be applied. In this work, we adopted the distance-scaling method that is based on continuous deformation of the original rugged energy hypersurface to obtain a smoothed surface. The method has been applied successfully to predict the structures of simple motifs, such as the three-helix bundle structure of the 10-58 fragment of staphylococcal protein A in de novo folding simulations and more complicated motifs in inverse-folding simulations. Received: 24 April 1998 / Accepted: 4 August 1998 / Published online: 2 November 1998     

Ab initio studies on the mechanism of dimerization reactions of ketene imine and bis(trifluoromethyl)ketene imine

The dimerization reactions of ketene imine and bis(trifluoromethyl)ketene imine were studied theoretically. All the dimerization processes take place in a concerted but asynchronous manner, each proceeding through a four-membered ring transition state. For the ketene imine dimerization reactions, three different processes have almost equal activation barriers, while for the three bis(trifluoromethyl)ketene imine dimerization processes the reaction giving symmetrical a four-membered heterocyclic product has the lowest activation barrier. Received: 15 July 1998 / Accepted 3 September 1998 / Published online: 17 December 1998     

Molecular dynamics simulations of the isolated domain 1 of annexin I

Annexin molecules consist of a symmetrical arrangement of four domains of identical folds but very different sequences. Nuclear magnetic resonance (NMR) experiments on the isolated domains of annexin I in aqueous solution have indicated that domain 1 retains its native structure whereas domain 2 unfolds. Therefore these two domains constitute interesting models for comparative simulations of structural stability using molecular dynamics. Here we present the preliminary results of molecular dynamics simulations of the isolated domain 1 in explicit water at 300 K, using two different simulation protocols. For the first, domain 1 was embedded in a 46 ? cubic box of water. A group-based non-bonded cut-off of 9 ? with a 5–9 ? non-bonded switching function was used and a 2 fs integration step. Bonds containing hydrogens were constrained with the SHAKE algorithm. These conditions led to unfolding of the domain within 400 ps at 300 K. In the second protocol, the domain was embedded in a 62 ? cubic box of water. An atom-based non-bonded cut-off of 8–12 ? using a force switching function for electrostatics and a shifting function for van der Waals interactions were used with a 1 fs integration step. This second protocol led to a native-like conformation of the domain in accord with the NMR data which was stable over the whole trajectory (∼2 ns). A small, but well-defined relaxation of the structure, from that observed for the same domain in the entire protein, was observed. This structural relaxation is described and methodological aspects are discussed. Received: 10 May 1998 / Accepted: 4 August 1998 / Published online: 2 November 1998