MM2 Force Field Research Articles

Molecular mechanics (MM3) study of the conformations of ethyl esters of diastereoisomeric 3-substituted 4,4,4-trichloro-2-cyano-butanoic acids

Molecular mechanics calculation (MM3 force field) were used to study the conformations of diastereoisomeric pairs of ethyl esters of 3-substituted 4,4,4-trichloro-2-cyano-butanoic acids in order to test an assumption from 1H NMR spectra about their preferred conformations. On the basis of the most probable preferred conformation in each case, an assignment of the relative configurations of these newly synthesized compounds was made in the earlier study. The present computed most favorable conformations are in accord with the earlier qualitative considerations in all cases, thus validating the assignment of the configurations of the diastereoisomers made previously.

Conformations of silicon-containing rings. Part 3. Relative conformational energies of alkylated 1,3,5-trisilacyclohexanes as calculated from quantum chemical and molecular mechanics methods

The relative energies of the basic conformations for five series of Si-alkylated derivatives of 1,3,5-trisilacyclohexane 1 with methyl, ethyl, i-propyl and t-butyl alkyl groups have been calculated using quantum chemical (QC) methods (HF and RI-DFT) and the MM3 force field. The results were compared to those from previous NMR investigations. It was found that the QC methods predict for all 1-mono-, cis-1,3-di and cis–cis-1,3,5-tri-alkylated 1 the chair(eq) to be the lowest energy conformation. The QC methods also predict a preference for twisted conformation in the cases of trans-1,3-di- and cis–trans-1,3,5-tri- t-butylated 1. The QC results confirm earlier predictions from the NMR data. In contrast, MM3 fails to calculate relative conformational energies properly. The reason for its failure is discussed.

Ab initio and molecular mechanics (MM3) calculations of protonated-neutral diamine hydrogen bonds.

Ab initio calculations of cation-neutral diamine complexes have been carried out at the MP2/6-311+G** level. The geometry and energetics of the charge-reinforced hydrogen bond are analyzed with respect to the alkyl substitution of both the protonated and neutral nitrogen atoms, and these results have been used to improve the quality of the MM3(2000) force field. In addition, specialized hydrogen bond parameters optimized for MM3(2000) are presented. These parameters allow very accurate gas-phase modeling of the charge-neutral diamine environment. Molecular mechanics calculations can model effectively protonated amine-neutral amine hydrogen bonds in the gas phase and solution (continuum dielectric) through a combination of charge-dipole interactions and explicit hydrogen-bonding terms.

Molecular mechanics:the cross-conjugated carbonyl group in heterocyclic compounds. 3. Parameterisation (MM2) of the adjacent C=C bond: evaluation tests

In the MM2 force field, the definition of a new type of carbon (carbonyl atom, when it is cross-conjugated) has led to the reestimation of the mechanical parameters of the adjacent C(O)-O and C(O)-N bonds in fully-conjugated cyclic compouds: α-pyrones, δ-lactones, and conjugated “lactams”. New parameters, based on the study of 97 bonds, are presented here for the similar adjacent C(O)-C bond in the same compounds. Comparison of calculated bond lengths to experimental X-ray bond lengths shows that, statistically, the results are substantially improved but the dispersion remains large. Full optimisation of the molecules concerned shows that in some cases the errors accumulate on the C(O)-O bond which is more sensitive to errors in the evaluation of its own π bond order. The origins of the discrepancies are discussed. Using caffeine as a test molecule, the MM2 method with the parameters proposed here, appears less acurate than the ab initio and DFT methods (both with 6–31G**basis) but still better than the semi-empirical methods (AM1-PM3).

Structure and conformational analysis of new arylpiperazines containing n-butyl chain

X-ray structure studies and conformational analysis were performed for three 1-arylpiperazine derivatives containing n-butyl chain, namely 1,4-benzoxazin-3(4H)-one, 1,2-benzoxazolin-3-one, and 1,3-benzoxazolin-2,4-dione. The extended conformation of the molecules in the crystals is delimited by the stacking and C–H⋯Cl interactions. Molecular modelling in two force fields (MM3 and TRIPOS) with different methods of conformational surface examination was tested. The conformational calculation with MM3 force field and stochastic search examination for the molecules like arylpiperazines seems to be much more satisfactory. It indicates that the folded form of 1-arylpiperazines is energetically favoured; however, the extended form is not far from the energy minimum.

Conformational analysis of N-benzylformamide

The potential energy surfaces (PES's) at different levels of ab initio electronic structure theory with correlation effects included are reported for rotation about the N(amide)–C(sp3) and C(sp3)–C(aryl) bonds in N-benzylformamide. Fully optimized geometries are in good agreement with crystal structure data and PES's are consistent with the experimental dihedral angle distributions. The results are used to assign MM3 force field parameters to allow calculation on N-benzyl substituted amides.

Parameters for the amber force field for the molecular mechanics modeling of the cobalt corrinoids

Additional parameters for the amber force field have been developed for the molecular mechanics modeling of the cobalt corrinoids. Parameter development was based on a statistical analysis of the reported structures of these compounds. The resulting force field reproduces bond lengths, bond angles, and torsional angles within 0.01 Å, 0.8°, and 4.0° of the mean crystallographic values, respectively. Parameters for the Co–C bond length and the Co–C–C bond angle for modeling the alkylcobalamins were developed by modeling six alkylcobalamins. The validity of the force field was tested by comparing the results obtained with known experimental features of the structures of the cobalt corrinoids as well as with the results from their modeling using a parameter set for the MM2 force field that has been previously developed and extensively tested. The amber force field reproduces the structures of the cobalt corrinoids as well as the MM2 force field, although it tends to underestimate the corrin fold angle, the angle between mean planes through the corrin atoms in the northern and southern half of the molecules, respectively. The force field was applied to a study of the structures of 5′-deoxy-5′-(3-isoadenosyl)cobalamin, 2′,5′-dideoxy-5′-adenosylcobalamin and 2′,3′,5′-trideoxy-5′-adenosylcobalamin. This expansion of the standard amber force field provides a force field that can be used for modeling the structures of the B 12-dependent proteins, the structures of some of which are now beginning to emerge. This was verified in a preliminary modeling of the coenzyme B 12 binding site of methylmalonyl coenzyme A mutase.

Expanding cavitand chemistry: the preparation and characterization of [n]cavitands with n>=4.

The preparation of cavitands composed of 4, 5, 6, and 7 aromatic subunits ([n]cavitands, n=4-7) is described. The simple, two-step synthetic procedure utilized readily available starting materials (2-methylresorcinol and diethoxymethane). The two cavitand products having 4 and 5 aromatic subunits exhibited highly symmetric cone conformations, while the larger cavitands (n = 6 and 7) adopt conformations of lower symmetry. 1H NMR spectroscopic studies of [6]cavitand and [7]cavitand revealed that these hosts undergo exchange between equivalent conformations at room temperature. The departure of these two cavitands from cone conformations is related to steric crowding on their Ar-O-CH2-OAr bridges and is predicted by simple molecular mechanics calculations (MM2 force field). X-ray diffraction studies on single crystals of the [4]cavitand, [5]cavitand, and [6]cavitand hosts afforded additional experimental support for these conclusions.

Temperature effects on the UV–Vis electronic spectrum of trans‐stilbene

AbstractThe ultraviolet (UV)–Visible absorption spectrum of trans‐stilbene (tS) is computed at different temperatures by coupling molecular dynamics (MD) simulations with the classical MM3 force field to ZINDO/S‐CIS calculations of vertical excitation energies and transition dipole moments. The selection of a large number of structures along the MD trajectories enables a consistent treatment of temperature effects in the vacuum, whereas the ZINDO/S‐CIS calculations permit a reliable treatment of electron correlation and relaxation, taking account of multistate interactions in the final state. Thermal motions are found to alter very differently the width and shape of bands. Structural alterations such as the stretching and the torsion of the vinyl single and double bonds very strongly influence the appearance of the first valence state, pertaining to the highest occupied and lowest unoccupied molecular orbital (HOMO–LUMO) transition. At temperatures less than 400 K, these are found to yield a merely Gaussian and very pronounced thermal broadening of the related band (A), up to nearly 30 nm, together with a minor blue shift of its maximum λmax. In contrast, a red shift by several nanometers occurs due to thermal motions for the remaining three valence bands. As can be expected, the broadening intensifies at higher temperatures, and for the A‐band, becomes markedly asymmetric when T exceeds 400 K. The combination of MD(MM3) and ZINDO/S‐CIS computations enables also consistent calculations of hot bands, which are forbidden by symmetry at 0 K. © 2001 John Wiley & Sons, Inc. Int J Quantum Chem, 2001

C(sp2)−C(Aryl) Bond Rotation Barrier in N-Methylbenzamide

The potential energy surfaces at different levels of ab initio electronic structure theory with correlation effects included are reported for rotation about the C(sp2)−C(aryl) bond in N-methylbenzamide. The results reveal a minimum at a CCCO dihedral angle of ±28° with barrier heights (MP2/aug-cc-pVTZ//BLYP/DZVP2/A2) of 0.48 kcal/mol at 0° and 2.80 kcal/mol at 90°. Fully optimized geometries are in good agreement with crystal structure data, and potential energy surfaces are consistent with the experimental dihedral angle distribution. The results are used to assign MM3 force field parameters to allow calculation on N-methylbenzamide and other benzamide derivatives.

Molecular mechanics (MM3) calculations on phosphonamidate compounds

Phosphonamidate compounds are regarded as transition-state analogs for amide hydrolysis reactions and can be used as potent haptens to elicit catalytic antibodies. The MM3 force field has been extended to cover these compounds, based on the structures, conformational energies, and vibrational analyses from MP2/6-31G∗ or B3LYP/6-31G∗ calculations. It was necessary to include a “trans-lone pair effect” in the MM3 force field so that the conformational dependence of the N–P and P–C bond lengths could be reproduced. This effect is similar to the Bohlman effect and the anomeric effect. The MM3-calculated molecular structures agree well with the quantum mechanics results, and the conformational equilibria and vibrational spectra are in fair agreement.

Relative stabilities of cholestadienes calculated by molecular mechanics and semi-empirical methods: application to the acid-catalyzed rearrangement reactions of cholesta-3,5-diene

The study of geochemical transformations undergone by ‘biological markers’ after their incorporation into sediments is an important field of organic geochemistry. Combined with laboratory simulation experiments, molecular mechanics calculations have been shown to be very useful to establish the reaction pathways, and to predict intermediate components and stable reaction end products, especially in the case of the acid-catalyzed isomerization reactions of steroid and terpenoid hydrocarbons. Many commercially available softwares are able to optimize (minimize) the geometries of molecules and compute some of their thermodynamical data with either molecular mechanics (MM) or semi-empirical methods of quantum chemistry. In order to verify the reliability of these methods, we have computed the relative thermodynamic stabilities of a large number of steradiene isomers with MM3 (Tripos Inc.), MM+ (HYPERCHEMTM) and MM2 (Chem3D, CambridgeSoft Corp.) empirical force fields, and with AM1 and PM3 (HYPERCHEMTM) semi-empirical methods. The calculation results of thermodynamic stabilities of steradiene isomers are used to explain the compounds produced by the rearrangement of cholesta-3,5-diene when treated with p-toluenesulfonic acid in acetic acid at 70°C. The end products, namely the spirosteradienes 7–8, obtained by this treatment are the most stable steradiene isomers according to all computational methods. The relative thermodynamic stabilities of cholestadienes are also consistent with the mechanism postulated for the spirosteradiene formation proceeding through a pathway including cholestadienes 2–6 as intermediates.

New regioselective multicomponent reaction: one pot synthesis of spiro heterobicyclic aliphatic rings.

In the context of our high-throughput organic synthesis program, we have studied the reactivity of special beta-keto esters toward the Biginelli reaction. We have found that a cyclic beta-keto ester reacts with one molecule of urea and two molecules of aldehyde to give a new family of spiro heterobicyclic aliphatic rings in good yields. Interestingly, the Biginelli product was not detected. After analysis of products using HPLC, 1H NMR, and 13C NMR, we have found that the reaction is driven by a regio-specific condensation of two molecules of aldehyde with the other reagents to afford only products harboring substituents exclusively in cis configuration. Monte Carlo minimization studies using MM2 force field suggest that cis products are energetically more stable than the trans counterparts. Together with previously reported data, these results suggest that the trans products were not obtained as result of steric hindrance produced by the equatorial position of one of the ring substituents. This new reaction is useful for high-throughput organic synthesis. Indeed, the new scaffold can be used to introduce additional groups in the molecules through remaining functional groups by a "domino strategy".

Molecular mechanics (MM3) study of the conformations of methyl esters and N,N-dimethylamides of diastereoisomeric 4-cyano-3,4-diphenyl-butanoic acids

Molecular mechanics (MM3 force field) was used to examine an unexpected observation by NMR for a preference of conformations with synclinal protons around the C(3)–C(4) bond in methyl esters and dimethylamides of diastereoisomeric 4-cyano-3,4-diphenyl-butanoic acids. After the reoptimization of three torsional parameters, related to structural units containing a cyano group, we obtained a good correlation between the MM3 computed populations of the conformations and the estimates from vicinal coupling constants. The electrostatic interactions have the decisive contribution for lowering the energies of the preferred conformations.

Interpretation of the Diastereoselectivity of the Cyclopropane Formation Involving π-Allyl Palladium Complexes Based on Molecular Mechanics Calculations

The diastereoselectivity of the base-induced cyclization of 2-amino-4-chlorobutyronitrile derivatives and of the palladium (0) catalyzed tandem alkylation and cyclization of ( E)- and ( Z)-1,4-dichlorobut-2-enes, providing suitable precursors of asymmetric 2,3-methanoamino acids, was interpreted by means of molecular mechanics calculations based on the MM2 force field. The dummy atom concept for the construction of η 3-allyl palladium complexes and a new parameter set for the calculation have been used. The observed diastereoselectivity which resulted from simple kinetic or thermodynamic control, can be however altered in some cases by the palladium-induced reversibility of the three-membered ring formation.

Molecular mechanics study of β-cyclodextrin 6-O-monobenzoate inclusion complexes

Calculations have been done on β-cyclodextrin 6-O-monobenzoate and its complexes using molecular mechanics MM2 force field. The guest molecules involved were n-hexane, n-heptane, n-octane, cyclohexane, methylcyclohexane, cyclooctane and methylcyclooctane. Owing to lack of dipole–dipole and hydrogen-bonding interactions in the inclusion complexation of the modified cyclodextrin, the calculations of the geometry of the complexes and the inclusion process indicated that the complex formation is stabilized by van der Waals interaction. The energy differences of the modified cyclodextrins by calculation show that the size, shape, conformation of the guest molecules play significant roles in the inclusion complexation.

A conformational study of the xyloglucan oligomer, XXXG, by NMR spectroscopy and molecular modeling

A structural study of the XXXG xyloglucan heptasaccharide (X = α-D-Xylp(1 → 6)-β-D-Glcp and G = β-D-Glcp) isolated from apple fruit has been undertaken with nmr and molecular mechanics methods. Quantitative 400 MHz nmr data including nuclear Overhauser effect spectroscopy (NOESY) volumes were recorded at both 6 and 20°C. In spite of severe overlapping of resonances, it was possible to estimate summed NOEs for the majority of the anomeric and glucosyl methylene protons. An ensemble-average population of preferred geometries has been established with the CICADA conformational searching algorithm associated with the MM3 force field. Comparison of the theoretical data obtained by back-calculation of the NOESY volumes from the ensemble-average distance matrix program and motional models based on the Stokes–Einstein–Debye relation satisfactorily reproduce the experimental data. Conformational averaging about the mainchain glycosidic linkages includes both the syn and anti conformers and a minor gauche–gauche population is highly probable. The theoretical data overestimate the syn preference of the Glcc → Glcb linkage as well as the Glcc GT rotamer population. Finally, both the motional models and the conformational search indicate a fairly rigid backbone and greater flexiblity for the xylose side chains. © 2000 John Wiley & Sons, Inc. Biopoly 54: 11–26, 2000

Conformational behavior of hyaluronan in relation to its physical properties as probed by molecular modeling.

Hyaluronan (HA) is a linear charged polysaccharide whose structure is made up of repeating disaccharide units. Apparently conflicting reports have been published about the nature of the helical structure of HA in the solid state. Recent developments in the field of molecular modeling of polysaccharides offer new opportunities to reexamine the structural basis underlying the formation and stabilization of ordered structures and their interactions with counterions. The conformational spaces available and the low energy conformations for the disaccharide, trisaccharide, and tetrasaccharide segments of HA were investigated via molecular mechanics calculations using the MM3 force field. First, the results were used to access the configurational statistics of the corresponding polysaccharide. A disordered chain having a persistence length of 75 A at 25 degrees C is predicted. Then, the exploration of the stable ordered forms of HA led to numerous helical conformations, both left- and right-handed, having comparable energies. Several of these conformations correspond to the experimentally observed ones and illustrate the versatility of the polysaccharide. The double stranded helical forms have also been explored and theoretical structures have been compared to experimentally derived ones.

Molecular modelling of solid-supported polymerisation of 4-(5-hexynyloxy)-β,β-dibromostyrene

Solid-supported hyperbranched polymerisation of 4-(5-hexynyloxy)-β,β-dibromostyrene was modelled using MM2 force field. The results show that at least up to the 6th generation there is no excessive strain due to the steric hindrances in the molecule. Moreover, it seems that steric energy per atom tends to a limit with the number of generation. Steric hindrance between a single bound hyperbranched molecule and the support are far less than the attractive van der Waals interactions, independent of the nature of the polymeric support and the generation number of dendritic molecule. The only important steric hindrance was found between two bound hyperbranched molecules attached to adjacent active sites of the polymeric support. In this particular case the distance separating two attached hyperbranched molecules is strongly affected by the steric interactions.

Photochemistry of valerophenone in solid solutions

Photoreactivity of valerophenone was investigated in frozen solid solvents: benzene, cyclohexane, t-butanol, hexadecane, and water. Different product and mass distributions were followed during the course of the photoreaction. It was evidenced that a portion of ketone molecules is almost unreactive in the solid state due to physical restraints of the solid solvent cavity. Free rotation along the C–C bonds becomes difficult inside the cavity and it is probable that larger conformational changes are totally restricted. It was shown that a fraction of molecules having the favorable conformation for hydrogen abstraction reacts with the same photochemical efficiency no matter what solvent was used. The elimination/cyclization ratio of the Norrish Type II reaction was studied as a function of temperature. Variation of the ratios, characteristic for each solvent, diminished with decreasing temperature what has been rationalized in terms of the effective reaction cavity. The semi-empirical PM3 method and molecular mechanics MM3 force field calculations were performed to evaluate stabilities of the ground state valerophenone conformations.