Stereochemical studies on germacrenes: an application of molecular mechanics calculations

Molecular mechanics calculations are successfully carried out to evaluate relative stabilities of each conformation of germacrene-A ($\text{1}$), germacrene-B ($\text{2}$) and hedycaryol ($\text{3}$) in their ground states and transition states. Thus, the calculation results on each transition state model indicate that the elements are formed from the corresponding germacrenes through the most stable transition states (CC), regardless of the most stable conformers in each ground state.     

Conformational analysis of synthetic neolignans active against leishmaniasis,using the molecular mechanics method (MM2)

Conformational analysis of 20 neolignans was performed to determine the most probable conformer that may fit the receptor. The molecular mechanics method (MM2) was employed to construct conformational maps in both a vacuum and a biological environment. Boltzmann's distribution among several local minima was calculated. © 1997 by John Wiley & Sons, Inc. J Comput Chem 18: 712–721, 1997     

Electrostatic interactions in molecular mechanics (MM2) calculations via PEOE partial charges I. Haloalkanes

The PEOE (partial equalization of orbital electronegativity) procedure has been modified slightly and reparametrized for haloalkanes to calculate partial atomic charges suitable for evaluation of dipole moments and electrostatic energies in conjunction with molecular mechanics (MM2) calculations. Dipole moments of 66 haloalkanes are calculated with an average absolute deviation of 0.14 D from experimental values. The conformational energies of 40 compounds have been calculated and the agreement with experimental data is generally good and compares well with calculations by the IDME (induced dipole moment and energy) method. In addition, carbon and proton charges correlate well with C-1s core binding energies and ¹H-NMR (nuclear magnetic resonance) shifts for halomethanes. The most striking benefit of treating electrostatics through a set of partial charges compared to the standard MM2 bond dipole approach is demonstrated by calculations on 1,4-disubstituted cyclohexanes, for which standard MM2 fails to predict the most stable conformation.     

Ab initio and molecular mechanics (MM2 and MM3) calculations of nonconjugated positively charged nitrogen-containing compounds

High-level ab initio calculations have been performed on N-methyl-N-methyleneammonium and related compounds to obtain accurate rotational barriers, structures, and vibrational frequencies. The 6-31G** basis set has been utilized at the Hartree-Fock level of theory for these calculations because little experimental data are available. The MM2(91) and MM3(94) force fields have been parameterized to include these nonconjugated charged nitrogen-containing compounds. Molecular mechanics geometries and vibrational frequencies compare well with the ab initio results. © 1995 John Wiley & Sons, Inc.     

Ab initio and molecular mechanics (MM2 and MM3) calculations of positively charged conjugated nitrogen-containing compounds

Ab initio calculations have been carried out on s-trans-N-vinylmethyleneammonium, pyridinium, and related compounds to obtain rotational barriers, structures, and vibrational frequencies. The restricted Hartree-Fock (RHF) level of theory with 6-31G** basis set was used for these calculations. In addition, the MM2(91) and MM3(94) force fields have been parameterized to calculate these positively charged nitrogen-containing compounds. A bond order term was incorporated in the force field to reproduce accurately the rotational barriers of s-trans-N-vinylmethyleneammonium and related compounds. Molecular mechanics geometries and vibrational frequencies compare well with those calculated by ab initio methods. © 1996 by John Wiley & Sons, Inc.     

Conformational analysis of dehydrodidemnin B (aplidine) by NMR spectroscopy and molecular mechanics/dynamics calculations.

Dehydrodidemnin B (DDB or aplidine), a potent antitumoral natural product currently in phase II clinical trials, exists as an approximately 1:1 mixture of two slowly interconverting conformations. These are sufficiently long-lived so as to allow their resolution by HPLC. NMR spectroscopy shows that this phenomenon is a consequence of restricted rotation about the Pyr-Pro(8) terminal amide bond of the molecule's side chain. The same technique also indicates that the overall three-dimensional structures of both the cis and trans isomers of DDB are similar despite the conformational change. Molecular dynamics simulations with different implicit and explicit solvent models show that the ensembles of three-dimensional structures produced are indeed similar for both the cis and trans isomers. These studies also show that hydrogen bonding patterns in both isomers are alike and that each one is stabilized by a hydrogen bond between the pyruvyl unit at the terminus of the molecule's side chain and the Thr(6) residue situated at the junction betwen the macrocycle and the molecule's side chain. Nevertheless, each conformational isomer forms this hydrogen bond using a different pyruvyl carbonyl group: CO(2) in the case of the cis isomer and CO(1) in the case of the trans isomer.     

Molecular mechanics (MM2) calculations and cone angles of phosphine ligands

Molecular mechanics (MM2) calculations were performed on 54 conformations of 18 phosphines (PH₃; PH_3−nR_n, where n = 1,…3, and R = Me and Et, n = 1 or 2 and R =ⁱPr, and n = 1 and R =^tBu, PMe₂Et, PMeEt₂, and PPhMe₂, and PPh₂R where R = Me, Et, ⁱPr, ^tBu and Ph). The results are compared to those previously obtained from MINDO/3 and MNDO calculations, and to experimental data. Single conformer cone angles and weighted average cone angles were calculated from MM2 optimized geometries employing Tolman's general definition, and they are compared to Tolman's values, MINDO/3 results, and T.L. Brown's E_R values. Of the cone angle definitions used, the weighted average values are suggested as the best single representation of phosphine ligand sizes. The steric parameters (cone angle and E_R values) alone, and in conjunction with electronic parameters, are correlated with experimental data.     

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.     

Application of parallel processing techniques to improving the efficiency of MM2 molecular mechanics calculations

The application of parallel processing techniques to molecular mechanics calculations is evaluated. Using the standard molecular mechanics package, MM2, four different parallel versions of the program are implemented in a four-processor computing environment. A set of 529 test structures is used to compare the efficiency of the parallel versions of MM2 to a standard serial version of the program. Statistics describing execution times and program execution cycles are gathered and analyzed. The effects of parallel processing overhead and computer system load are explored, and the practical utility of parallel processing in molecular mechanics is estimated. The results of these parallelization experiments indicate that for geometry optimizations requiring significant amounts of computing time an improvement in program execution speed approaching 50% is realizable. © 1993 John Wiley & Sons, Inc.     

Conformational study of the cembranolide diterpene denticulatolide by molecular mechanics method

The most stable conformation of denticulatolide (1), an ichthyotoxic cembranolide, obtained as a major metabolite of the soft coral, Lobophytum denticulatum, was given by molecular mechanics calculations and it was confirmed by ¹H NMR measurement. The geometry of 14-membered carbocycle of 1 was found to be different from that of derivative (2) especially around the juncture part of γ-lactone. The molecular mechanics calculation successfully reproduced the conformational changes between 1 and 2.     

Coupled semiempirical quantum mechanics and molecular mechanics (QM/MM) calculations on the aqueous solvation free energies of ionized molecules

The aqueous solvation free energies of ionized molecules were computed using a coupled quantum mechanical and molecular mechanical (QM/MM) model based on the AM1, MNDO, and PM3 semiempirical molecular orbital methods for the solute molecule and the TIP3P molecular mechanics model for liquid water. The present work is an extension of our model for neutral solutes where we assumed that the total free energy is the sum of components derived from the electrostatic/polarization terms in the Hamiltonian plus an empirical “nonpolar” term. The electrostatic/polarization contributions to the solvation free energies were computed using molecular dynamics (MD) simulation and thermodynamic integration techniques, while the nonpolar contributions were taken from the literature. The contribution to the electrostatic/polarization component of the free energy due to nonbonded interactions outside the cutoff radii used in the MD simulations was approximated by a Born solvation term. The experimental free energies were reproduced satisfactorily using variational parameters from the vdW terms as in the original model, in addition to a parameter from the one-electron integral terms. The new one-electron parameter was required to account for the short-range effects of overlapping atomic charge densities. The radial distribution functions obtained from the MD simulations showed the expected H-bonded structures between the ionized solute molecule and solvent molecules. We also obtained satisfactory results by neglecting both the empirical nonpolar term and the electronic polarization of the solute, i.e., by implementing a nonpolarization model. ©1999 John Wiley & Sons, Inc. J Comput Chem 20: 1028–1038, 1999     

Conformational energy analysis of substituted diphenylethanes: Part II. Empirical energy calculations on stilbene dihalogenides

The geometry and energy of the stable conformations of the isomeric forms of 1,2-halogeno-1,2-diphenylethanes have been obtained by means of empirical energy functions. A minimization of the conformational energy with respect to the torsion angles and the valence angles around the asymmetrically substituted carbon atoms has been carried out. The evaluated populations of the stable conformations showed good agreement with available experimental data. CNDO/2 calculations on the low-energy conformations of the isomeric forms of 1,2-difluoro-, 1,2-fluorochloro-, and 1,2-dichlorodiphenylethane have been carried out. These yielded improved estimates of the dipole moments for the dichloro isomers.     

Conformational analysis of e,e-germacranes by the method of molecular mechanics

Molecular mechanics calculations have been made in order to analyze the reasons for the realization of one of four conformations in sesquiterpene germacranes and to evaluate their relative stabilities in the most probable states. Conformational transitions in unsubstituted 6(7)- and 7(8)-germacrolides and unlactonized germacranes have been modeled.Institute of the Chemistry of Plant Substances, Academy of Sciences of the Republic of Uzbekistan, Tashkent, fax (3712) 40 64 75. Translated from Khimiya Prirodnykh Soedinenii, No. 3, pp. 379–382, May–June, 1997.     

Molecular mechanics (MM2) calculations on peptides and on the protein Crambin using the CYBER 205

The MM2 potential functions for amides and peptides have been further extended by examining the experimental crystal structures for cyclo-(-Ala-Ala-Gly-Gly-Ala-Gly-), I, and cyclo-(-Ala-Ala-Gly-Ala-Gly-Gly-), II. The force field obtained was then applied to a study of the structure of the hydrophobic protein Crambin, for which a high resolution crystal structure is available. The energy minimization was carried out using a version of MM2 adapted to the CYBER 205.     

Conformational analysis of polymethylated derivatives of piperidine by the method of molecular mechanics

The conformational (steric) energies of different conformers and thus the type of dominant conformation were determined by the method of molecular mechanics for polysubstituted derivatives of piperidine. The chair conformation dominates for polymethylated 4-piperidines. The half-chair conformation is preferred for 1-methyl-3-methylene-4-piperidone, and the sofa conformation is preferred for analogous polymethylated enones.Translated from Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya, No. 1, pp. 91–97, January, 1991.     

Comparative quantum mechanics/molecular mechanics (QM/MM) and density functional theory calculations on the oxo-iron species of taurine/alpha-ketoglutarate dioxygenase

We present here the first quantum mechanical/molecular mechanics (QM/MM) studies of taurine/alpha-ketoglutarate dioxygenase (TauD) enzymes. Our studies are focused on the chemical properties of the oxo-iron species and the effect of the protein environment on its structural and electronic behavior. Although the active site region of TauD is very polar with many key hydrogen bonding interactions and salt bridges, the actual effect of the protein environment on the ordering and relative energies of the possible spin state structures is found to be quite small. Optimized geometries are very close to ones observed with density functional theory models that did not take the protein environment into consideration. The calculations show that protonation of the histidine ligands of iron is essential to reproduce the correct electronic representations of the enzyme. Hydroxylation studies of taurine by the oxo-iron active species predict that it is a very efficient catalyst that reacts with substrates via low reaction barriers.