MM2 Force Research Articles

Using artificial neural networks to develop molecular mechanics parameters for the modelling of metalloporphyrins. III. Five coordinate Zn(II) porphyrins and the metalloprophyrins of the early 3d metals

Artificial neural networks (ANNs) are used as an aid in developing force field parameters for modelling, using molecular mechanics methods and the MM2 force field, the porphyrins of the early transition metals, Sc(III), Ti(II), Ti(III), Ti(IV), V(II), V(III), V(IV), Cr(III), Cr(IV) and Cr(V), in which the metal is either five- or six-coordinate. The porphyrin ring itself was modelled with previously derived parameters and attention was focussed on deriving parameters to model the coordination sphere of the metal. By modelling five-coordinate Zn(II) porphyrins with an axial pyridine ligand, for which there are many structures, we demonstrate that the length of the metal–N porph bond is relatively insensitive to the length of the metal–N axial bond, and vice versa. There are relatively few crystal structures of the early 3d metalloporphyrins available and very few which contain the same axial ligand. Hence, preliminary parameters for modelling a wide variety of axial ligands are reported; these were typically derived by initially setting the strain free bond length and bond angles involving the metal and the axial donor atom to the crystallographically observed value, and varying the bond stretching and angle bending parameter, or the strain free bond length and bond angles iteratively, until the bond length and angles were reproduced to within 0.01 Å and 2.5°, respectively. Since the modelling of the [Zn(porphyrin)(pyridine)] complexes demonstrated the relative insensitivity of the equatorial metal–ligand parameters to the axial metal–ligand parameters and vice-versa, the paucity of structures and hence the necessarily preliminary values of the parameters for the modelling of the axial ligands did not preclude the development of parameters for the equatorial ligands. The strain free bond length l o, and the stretching force constant k s for the metal–N porph bond length was varied in a grid-like pattern. The mean difference between the metal–N porph bond length observed experimentally and determined by MM was defined as the error function. The minimum value of the error function was found using ANNs. Modelling the structures with the values of k s and l o that correspond to the minimum of the error function gave mean metal–N porph bonds that differed from crystallographically observed values by at most 0.008 Å, within the experimental standard deviation of this parameter. The deviations from planarity found in many of the modelled structures were usually well reproduced in the modelling. Where significant differences were noted, these could sometimes (but not always) be shown to be due to packing forces in the crystal lattice. As expected, the orientation of axial ligands and substituents on the periphery of the porphyrin ring was often significantly different in the modelled and the solid-state structure because of the conformational freedom of these groups.

Tetracycline and its analogues as inhibitors of amyloid fibrils: searching for a geometrical pharmacophore by theoretical investigation of their conformational behavior in aqueous solution

Tetracycline (TC) and its derivatives have recently been proposed as a new class of antagonists in prion diseases as they prevent the aggregation of prion protein peptides and their acquisition of protease resistance in vitro and in vivo. Looking for relationships between conformational flexibility and biological activity, we searched for a geometrical pharmacophore by investigating, in aqueous solution, the conformational behavior of 15 TCs in both the zwitterionic and the anionic forms. For TC similar conformational flexibility was found for the two forms and two main conformational families were detected, an extended and a folded conformation characterized by different intramolecular hydrogen-bond networks. On comparing the Molecular Mechanics results with the ab initio ones and the experimental evidence, it can be seen that the conformational behavior of TC is reasonably well predicted by the MM2 force field, whereas the conformational energies provided by the Amber force field are unreliable. The conformational analysis of the other TC derivatives was then performed by the MM2 force field. As a result, their conformational behavior was similar to that observed for TC itself. Despite the hydronaphthacene moiety's conformational flexibility, no geometrical pharmacophore was found among the TCs, i.e. properties other than geometrical ones should play a crucial role in determining their anti-fibrillogenic ability.

Pentacoordinated Cu(II)/Zn(II) complexes bearing macrocyclic skeleton: synthesis, spectroscopic and molecular structure optimization studies

2,6-Diacetylpyridine and 1,2-diaminoethane in the presence of copper(II) and zinc(II) chlorides containing a few drops of acetic acid were condensed into compositions [CuLH 2] 2·2HCl·H 2O ( 1), [Cu 2LPyz] 2·2HCl·4CH 3COCH 3 ( 2) [CuZnLPyz] 2·2HCl·2CH 3COCH 3·10H 2O ( 3) and [ZnL’Cl] 3·3HCl·3H 2O ( 4) substantiated by elemental analyses, IR, UV–vis, 1H NMR and FAB mass spectral data. Demetallation of a Ni(II) complex (isolated as above) afforded macrocyclic skeleton LH 4, whereas L’ symbolizes a skeleton of the ligand containing only ethylenediamine and 2,6-diacetylpyridine. Molecular structure optimization using MM2 force field calculations for the complexes revealed distorted square pyramidal geometry around Cu(II) centers in complexes 1 and 2 and tetrahedral geometry around Cu(II) and Zn(II) centers with different degrees of distortion in complex 3 whereas three Zn(II) atoms (each in distorted square pyramidal geometry) attached via Cl bridges form a cyclic structure in complex 4. In complexes 1 and 2,Cu–Cu = 2.63–2.66 Å indicated the possibility of coupling between the two Cu(II) centers which has been supported by lower magnetic moment as well as ESR spectra showing half-field signal.

Rational design of original materials for the electrocatalytic hydrogenation reactions: concept, preparation, characterization, and theoretical analysis.

Original and versatile new materials for the electrocatalytic hydrogenation of organic compounds were designed. The materials consist of reticulated glassy carbon cathode electrodes in which the modified silica particles (average diameter 40-63 microm) were dynamically circulated. The modification of the silica surface is 2-fold. First, the silica is surface-modified using organic functions such as -OSi(CH3)2(CH2)3OCH2CH-(OH)(CH)2OH (SiO2-Diol), -OSi(CH3)2(CH2)7CH3 (SiO2-C8), and -OSi(CH3)2C6H5 (SiO2-Phenyl). Second, these silica particles were further modified by vapor phase deposition of nickel nanoaggregates (used as sites for hydrogen atoms and electric contacts with the electrode material), which does not destroy or alter the organic functionalization as demonstrated by thermogravimetric analysis-mass spectrometry and Raman, diffuse reflectance IR Fourier transform, and Auger electron spectroscopies. The new concept stems from relative adsorption and desorption properties of the organic molecules and their corresponding reduced products into the organic functionalization of the surface-modified silica. In this work, the electrocatalytic hydrogenation cyclohexanone was used to test the concept. The performances (amount of cyclohexanol vs time of generated electrolysis at constant current) are measured and compared for the various bonded organic functions of the silica surface listed above, along with the unmodified silica particles (but still containing nickel nanoaggregates) and the presence or absence of methanol in solution. The measurements of the adsorption isotherms of cyclohexanone, and the calculations of the interaction energies (MM3 force field) between the chemisorbed organic functions and the substrates, corroborate perfectly the electrocatalysis results.

Macromolecular flexibility

We explore the conformational space of a macromolecule that has interlocking flexible rings. The model molecule has two internal degrees of freedom. Four interconnected ten-fold rings in the molecule are closed at every step in a random-walk procedure. Rings are closed by following the trajectory of solutions to the set of simultaneous ring closure equations. We show there are three useful hierarchies in the conformational space. The first is the space sampled when only bond length and angle constraints are imposed, which almost covers the whole allowed two-dimensional conformational space. The conformational space is reduced significantly when van der Waals constraints are imposed. Finally, the conformational space shrinks further to a few discrete states when conformations are optimized using the MM3 force field. These results validate the fact that this approach, which involves searching conformations with only bond length, bond angle and van der Waals constraints followed by a minimization with a full force field, is effective in exploring the low-energy conformations of macromolecules.

Self-assembly of nanoscopic coordination cages using a flexible tripodal amide containing linker.

Flexible, nanoscopic 3D cages containing the amide functionality were prepared via coordination-driven self-assembly from palladium(II) based 90 degrees ditopic acceptor units and a tripod N,N',N''-tris(3-pyridyl)trimesic amide. Both cages were characterized by NMR ((31)P, (1)H) and electrospray ionization mass spectrometry. An MM2 force field simulation of one cage showed that the shape is likely pseudo trigonal bipyramidal with the diameter of the inner cavity of the cage about 1.9 nm.

Theoretical studies of hyperthermal O(3P) collisions with hydrocarbon self-assembled monolayers.

We present a dynamics study of inelastic and reactive scattering processes in collisions of hyperthermal (5 eV) O(3P) atoms with a hydrocarbon self-assembled monolayer (SAM). Molecular-dynamics simulations are carried out using a quantum mechanics/molecular mechanics (QM/MM) interaction potential that uses a high quality semiempirical Hamiltonian for the QM part and the MM3 force field for the MM part. A variety of products coming from reaction are identified, including H abstraction to generate OH, O atom addition to the SAM with subsequent elimination of H atoms, and direct C-C breakage. The C-C breakage mechanism provides a pathway for significant surface mass loss in single reactive events whereas the O addition-H elimination channel leads to surface oxidation. Reaction probabilities, product energy, and angular distributions are examined to gain insight on polymer erosion in low Earth orbit conditions and on fundamentals of inelastic and reactive hyperthermal gas-surface interactions.

A large gem‐dimethyl effect in the cyclization of ω‐phenylhydantoic acids: computational modeling of the gem‐dimethyl effect on the acid‐ or base‐catalyzed cyclization of hydantoic acids and esters

AbstractThe rates of the cyclization of methyl‐substituted 5‐phenylhydantoic acids were measured in acid solutions. A particularly strong gem‐dimethyl effect (GDME) was observed with the N‐methyl compounds amounting to an acceleration of six powers of ten for the 2,2,3‐trimethyl derivative. The variations in the free energies of activation for the cyclization of hydantoic acids and esters were modeled by the strain energies of the tetrahedral intermediates and of the reactants calculated by the MM3 force field. The neutral tetrahedral intermediate T0 was used for reaction series involving acid catalysis and the negatively charged intermediate T− for base catalysis. Very good agreement with the experimental GDME was obtained for the acid‐catalyzed cyclizations of the complete series of the N‐methyl‐substituted substrates, showing that the accelerations result from a greater strain increase in the reactants. The results with T− are closely parallel, indicating that the loss of GDME observed under base catalysis with 2,2,3‐trimethylhydantoate esters is not due to intramolecular strain in T−. A linear correlation (slope 1.22, r = 0.934) is obtained for a plot of the free energy variations against strain energies for the reaction series of 5‐phenylhydantoic acids when the data for the strongly deviating parent acid is excluded. Excellent LFERs are obtained between the reaction series of esters and acids. The observed large rate enhancements induced by N‐substituents explain the switches to cyclization routes in synthetic reactions. Copyright © 2004 John Wiley & Sons, Ltd.

Synthesis, NMR and conformational studies of fucoidan fragments. VI. Fragments, content of alpha-(1--->2)-bound fucobioside unit

A series of selectively sulfated di- and trisaccharide derivatives corresponding to the potential fragments of fucoidans with a (1-->2)-alpha-bound fucobioside unit were synthesized and studied by 1H and 13C NMR spectroscopy. NOE experiments and molecular modeling were used for a conformational analysis of the compounds synthesized. In the case of disaccharides, the experimental NOE values were found to agree with those obtained using modeling with the use of density functional theory (DFT) and differ from those resulting from modeling by the molecular mechanics MM3 force field. Trisaccharide fragments partially or completely sulfated in position 4 turned out to be correctly described by both MM3 force field and DFT computation. The English version of the paper: Russian Journal of Bioorganic Chemistry, 2004, vol. 30, no. 2; see also http://www.maik.ru.

Characterization of the preferred stereochemistry for the neuropharmacologic actions of antillatoxin.

Antillatoxin is a potent ichthyotoxin and cytotoxin previously discovered from the marine cyanobacterium Lyngbya majuscula. Ensuing studies of its mechanism of action showed it to activate the mammalian voltage-gated sodium channel at a pharmacological site that is distinct from any previously described. The structure of antillatoxin, initially formulated from spectroscopic information, was subsequently corrected at one stereocenter (C-4) as a result of synthesis of four different antillatoxin stereoisomers (all possible C-4 and C-5 diastereomers). In the current study these four stereoisomers, (4R,5R)-, (4S,5R)-, (4S,5S)-, and (4R,5S)-antillatoxin, were characterized in five different biological assay systems: ichthyotoxicity to goldfish, microphysiometry using cerebellar granule cells (CGCs), lactose dehydrogenase efflux from CGCs, monitoring of intracellular Ca(2+) concentrations in CGCs, and cytotoxicity to Neuro 2a cells. Across these various biological measures there was great consistency in that the natural antillatoxin (the 4R,5R-isomer) was greater than 25-fold more potent than any of the other stereoisomers. Detailed NMR studies provided a number of torsion and distance constraints that were modeled using the MM2 force field to yield predicted solution structures of the four antillatoxin stereoisomers. The macrocycle and side chain of natural (4R,5R)-antillatoxin present an overall "L-shaped" topology with an accumulation of polar substituents on the external surface of the macrocycle and a hydrogen bond between N(H)-7' and the C(O)-1 carbonyl. The decreased potency of the three non-naturally occurring antillatoxin stereoisomers is certainly a result of their dramatically altered overall molecular topologies.

Conformational preferences of 1,4,7-trithiacyclononane: a molecular mechanics and density functional theory study.

Conformational preferences of 1,4,7-trithiacyclononane were studied using a highly efficient sampling technique based on local nonstochastic deformations and the MM2(91) force field. The results show that conformers that the molecule adopts in the crystal state were found to be low-energy conformers (LECs) within 5 kcal mol(-1) of the global minimum. A conformation with C1 symmetry was the global minimum and the C3 and C2 conformations were calculated to be 0.03 and 1.78 kcal mol(-1) higher in energy, respectively. The structures were further minimized using Density Functional Theory (DFT) calculations with two different functionals. The C2 and the C1 conformations were found to be LECs with the C3 conformation more than 4.0 kcal mol(-1) above the global minimum. The relative energies and structural ordering obtained using the BP86 functional are in agreement with the previously reported relative energies calculated using second-order Moller-Plesset (MP2) ab initio calculations. With the energy ordering being dependent on the molecular mechanics force field used, the approach of MM-->DFT (searching exhaustively the available conformational space at the MM level followed by generating the energy ordering through DFT calculations) appears to be appropriate for thiacrown ethers.

Nucleation of organic semiconductors on inert substrates

We have adapted the microscopic theory of nucleation for the epitaxial growth of inorganic materials to the nucleation of organic small molecules on an inert substrate like the gate dielectric of an organic thin-film transistor. The parameters required to explore the model were calculated with the standard MM3 force field and also include experimentally determined vapor pressure data, as well as film growth data. Sufficient agreement is found between the experimentally determined equilibrium crystal shape and heats of sublimation on the one hand and the calculated parameters on the other hand. The growth of pentacene, tetracene, and perylene on inert substrates has been studied in terms of this theory, especially focusing on the two-dimensional (2D) to 3D nucleation transition. It is demonstrated that 3D nucleation leads to ill-connected grains, while 2D nucleated grains form continuous films suitable for charge transport. The analysis of this transition allows for the experimental determination of the molecule-substrate interactions for a given molecule on a given surface. It was found that the deposition conditions for 2D growth shift to less favorable substrate temperatures and deposition rates as the difference between interlayer interactions and molecule-substrate interactions increase and the intralayer interactions decrease. Moreover, those interactions affect the nucleation rate and therefore the ultimate 2D grain size that can be obtained.

Conformational Studies of the O-specific Polysaccharide of Shigella flexneri 5a and of Four Related Synthetic Pentasaccharide Fragments Using NMR and Molecular Modeling

As part of a program for the development of synthetic vaccines against the pathogen Shigella flexneri, we used a combination of NMR and molecular modeling methods to study the conformations of the O-specific polysaccharide (O-SP) of S. flexneri 5a and of four related synthetic pentasaccharide fragments. The NMR study, based on the analysis of 1H and 13C chemical shifts, the evaluation of inter-residue distances, and the measurement of one- and three-bond heteronuclear coupling constants, showed that the conformation of one of the four pentasaccharides is similar to that of the native O-SP in solution. Interestingly, inhibition enzyme-linked immunosorbent assay demonstrated that a protective monoclonal antibody specific for S. flexneri 5a has a greater affinity for this pentasaccharide than for the others. We carried out a complete conformational search on the pentasaccharides using the CICADA algorithm interfaced with MM3 force field. We calculated Boltzmann-averaged inter-residue distances and 3JC,H coupling constants for the different conformational families and compared the results with NMR data for all pentasaccharides. Our experimental data are consistent with only one conformational family. We also used molecular modeling data to build models of the O-SP with the molecular builder program POLYS. The models that are in agreement with NMR data adopt right-handed 3-fold helical structures in which the branched glucosyl residue points outwards.

Hetaryleneaminopolyols and Hetarylenecarbopeptoids: A New Type of Glyco‐ and Peptidomimetics. Syntheses and Studies on Solution Conformation and Dynamics.

AbstractFor Abstract see ChemInform Abstract in Full Text.

MM3 potential energy surfaces of trisaccharides. II. Carrageenan models containing 3,6-anhydro-D-galactose.

The adiabatic potential energy surfaces (PES) of six trisaccharides-namely 3,6-An-alpha-D-Galp-(1-->3)-beta-D-Galp-(1-->4)-3,6-An-alpha-D-Galp, beta-D-Galp-(1-->4)-3,6-An-alpha-D-Galp-(1-->3)-beta-D-Galp, and their derivatives sulfated on positions 2 and 4 of the beta-galactose unit-were obtained using the MM3 force field. Each PES was described by a single contour map for which the energy is plotted against the two psi glycosidic angles, given the small variations of the phi glycosidic torsional angle in the low-energy regions of disaccharide maps. In five of the six examples, the surfaces are those expected from the maps of the disaccharidic repeating units of carrageenans, with less important factors altering the additive effect of both linkages. However, when a sulfate group is present on C2 of a beta-galactose reducing end, a new low-energy minimum in a different region is produced, originated in a hydrogen bond between the first and third monosaccharidic moieties of the trisaccharide. The flexibility of the beta-linkages is nearly identical to that in their disaccharide counterparts, while that of the alpha-linkages is slightly reduced, independent of their presence closer or further away from the reducing end. A fair agreement is observed between the x-ray fiber diffraction analysis for a kappa-carrageenan double helix and the surfaces obtained for the trisaccharide analogs of that polymer.

Alcohols, ethers, carbohydrates, and related compounds. II. The anomeric effect.

The anomeric effect has been studied for a variety of compounds using the MM4 force field, and also using MP2/6-311++G(2d,2p) ab initio calculations and experimental data for reference purposes. Geometries and energies, including conformational, rotational barriers, and heats of formation were examined. Overall, the agreement of MM4 with the experimental and ab initio data is good, and significantly better than the agreement obtained with the MM3 force field. The anomeric effect is represented in MM4 by various explicit terms in the force constant matrix. The bond length changes are accounted for with torsion-stretch elements. The angle changes are accounted for with torsion-bend elements. The energies are taken into account with a number of torsional terms in the usual way. A torsion-torsion interaction is also of some importance. With all of these elements included in the calculation, the MM4 results now appear to be adequately accurate. The heats of formation were examined for a total of 12 anomeric compounds, and the experimental values were fit by MM4 with an RMS error of 0.42 kcal/mol.

Conformational Dynamics in Nitrogen‐Fused Azabicycles.

Using molecular mechanics (MM3 force field)-based methodology, conformational dynamics have been studied for 1-azabicyclo[2.2.0]hexane, 1-azabicylo[3.3.0]octane, and 1-azabicylo[4.4.0]decane. Obtained conformational schemes describe the flexibity of these parent azabicyles as well as permit us to estimate conformational mobility in related N-fused systems. Quantum mechanics ab initio calculations have been used in order to check the reliability of molecular mechanics-provided estimates of relative energy of conformers. The previous dynamic NMR (DNMR) data have been reinterpreted for some polycyclic alkaloids.

Conformational analysis of the exopolysaccharide from Burkholderia caribensis strain MWAP71: impact on the interaction with soils.

The strain MWAP71 of Burkholderia caribensis produces a branched charged exopolysaccharide (EPS) that is responsible for soil aggregation. Understanding the conformational properties of the isolated polysaccharide is a prerequisite for proper investigation of the interactions between the polysaccharide and the soil at the atomic level. The aim of this study is first to have an overall view of the flexibility of the backbone and then to ascertain the role played by side groups in the conformational properties of the main chain. Conformational analysis of each oligomeric segment of the polysaccharide has been performed by means of adiabatic mapping of the backbone glycosidic torsion angles using the MM3(92) force field. Substitution by an acetyl group or by a Kdo unit has only a slight effect on the potential energy surfaces of the fragment model compounds. Calculated partition functions, however, indicate that the overall flexibility is slightly larger for the substituted oligomers than for the unsubstituted ones. Prediction of selected average interproton distances from the AB and BC potential energy surfaces allows comparison between modeling results and NMR measurements performed on the ABC fragment. Agreement between the experimental and the predicted data suggests that the established surfaces correctly reflect the observed conformational behavior of such fragments and validate the modeling protocol. The above results have been extended to regular and disordered long polymer chains, differing in Kdo content. It is found that Kdo affects the helical conformations of the polysaccharide. The number of stable helices is considerably larger with Kdo than without Kdo. On the contrary, Kdo has only a moderate effect on unperturbed disordered conformations of the polysaccharide. Predicted persistence length of 70 A suggests that the polymer is semirigid with moderate extension. A further validation of the modeling results is obtained by the good concordance between this predicted value and the experimental one of 95 A, measured from light scattering and viscosity experiments. The results lead to an understanding of the interactions of this polysaccharide with soils.

Effect of Thermal Motions on the Structure and UV−Visible Electronic Spectra of Stilbene and Model Oligomers of Poly(p-Phenylene Vinylene)

In the present study, we investigate the influence of temperature on the width and location of bands in the UV−visible absorption spectra of oligomer chains of poly(p-phenylene vinylene) (PPV). These spectra have been computed by means of molecular dynamics (MD) simulations along with the classical MM3 force field, in conjunction with (Z)INDO/S-CIS calculations of vertical excitation energies and transition moments. In addition, the MD(MM3) computations enable consistent insights into the average structures of cis- and trans-stilbene, at temperatures ranging from 0 to 500 K. For trans-stilbene and larger PV-n oligomer chains converging to PPV, thermal motions at room temperature in the vacuum result in a constant broadening of bands by 24 nm (0.20 eV) at half the maximum. Compared with the trans-isomer, thermal broadening intensifies to 33 nm (0.44 eV) for cis-stilbene, due to enhanced steric effects. When accounting in addition for the outcome of vibronic broadening, the width of the first absorption band increases at 300 K to 33 nm (0.48 eV) for trans-stilbene and ∼46 nm (0.40 eV) for the largest PV-n chains. At last, upon studying a large molecular cluster reproducing the crystalline structure of trans-stilbene, it has been found that, although they strongly impede the rotations of phenyl rings and out-of-plane distortions, packing effects and steric hindrances in the solid phase lead to a limitation of the width of the first absorption band by 6 nm (0.07 eV) only at 300 K.

Implementation of a quantum mechanics/molecular mechanics approach in the parallel density functional program ParaGauss and applications to model copper thiolate clusters

Based on the integrated molecular orbital and molecular mechanics approach, we constructed a combined quantum mechanics (QM) and molecular mechanics (MM) method, by combining the parallel density functional program ParaGauss with the MM3 force field. We examined different ways to describe link atoms at the boundary between the QM and MM regions which we tested successfully on various organic molecules. We applied the new tool, intended for the description of metal–ligand interaction, to model Cu thiolate clusters. Separation at the first C–C bond was favored over a transition at the S–C bond, closer to the metal particle. We successfully checked the effect of different ligand orientations on the cluster geometry by comparison with QM calculations. Hybrid calculations correctly described geometric rearrangements to avoid steric stress of larger ligands. Thus, the QM/MM approach is also applicable when direct metal–metal interactions have to be treated.