分子力场进展

分子力学（简称ＭＭ）是近年来化学家常用的一种计算方法。与量子力学从头计算和半经验方法相比，用分子力学处理大分子可以大大节省计算时间，而且，在大多数情况下，用分子力学方法计算得到的分子几何构型参数与实验值之间的差值可在实验误差范围之内。所以，分子力学是研究生物化学体系的有效和可行的手段。分子力学的核心是分子力场。本文介绍了分子力场的量子力学背景、分子力场和光谱力场之间的关系。分子力场的一般形式、分力     

Molecular structure of 2-Amino-5-(1-methyl-5-nitro-2-imidazolyl)-1,3,4-thiadiazol (Megazol) and related compounds: A concerted study using X-ray crystallography,molecular mechanics,and semiempirical methods

A structural study of three nitroimidazoles was carried out using molecular mechanics, semiempirical methods, and X-ray crystallography. Structural features which might account for the high efficiency of1 (Megazol) as an antiparasitic drug and its opposite, the inactivity of its regiomers2 and3 were examined, i.e., coplanarity of the two rings, preferred conformations, and rotational barriers around the pivot bond between the two rings. For the three compounds an antiperiplanar conformation is preferred for the N(CH₃) and C-S bonds. For compounds1 and3, the rings are coplanar, with2 being somewhat twisted. The geometry obtained by molecular mechanics for compound1 is in excellent agreement with the X-ray structure, and greater confidence can be placed in this method than in semiempirical ones. Similarities observed on the LUMO positions, as well as rotational barriers lead to the conclusion that the differences in biological activity of these compounds do not rely on their ground state properties but rather on their subsequent reactions with oxygen. In addition, the calculations revealed significant structural information of a family of biological importance (nitroimidazoles) and constitute a comparative test for the MM2, AM1, and PM3 methods.     

Ab initio vibrational analysis of hexafluoroethane C2F6

Quantum mechanical geometry optimizations and the calculation of vibrational frequencies of hexafluoroethane have been performed at the HF/6-31G*, MP2/6-31G*, CCSD/cc-pVDZ, and B3LYP/6-31G* levels. The force fields obtained were scaled. The necessity is stressed of carrying out the detailed analysis of the vibrational spectra of small reference molecules to determine sets of scale factors which are transferable to quantum mechanical force fields of large molecules for the purpose of predicting their vibrational spectra.     

Electrostatic effects in enzyme catalysis: a quantum mechanics/molecular mechanics study of the nucleophilic substitution reaction in haloalkane dehalogenase

Combined quantum mechanics/molecular mechanics molecular dynamics simulations have been carried out to study the cleavage of the carbon–chlorine bond in 1,2-dichloroethane catalysed by haloalkane dehalogenase from Xanthobacter Autotrophicus GJ10. The process has been compared with an adequate counterpart in aqueous solution, the nucleophilic attack of acetate anion on 1,2-dichloroethane. Within the limitations of the model, mainly due to the use of a semiempirical Hamiltonian, our results reproduce the magnitude and characteristics of the catalytic effect. Comparisons of the enzymatic and in solution potentials of mean force reveal that, irrespective of the reference state, the enzyme shows a larger affinity for the transition state. The origin of this increased affinity is found in the differences in the electrostatic pattern created by the environment in aqueous solution and in the enzyme.Proceedings of the 11th International Congress of Quantum Chemistry satellite meeting in honor of Jean-Louis Rivail     

Molecular dynamics and free energy perturbation study of hydride-ion transfer step in dihydrofolate reductase using combined quantum and molecular mechanical model

We used molecular dynamics simulation and free energy perturbation (FEP) methods to investigate the hydride-ion transfer step in the mechanism for the nicotinamide adenine dinucleotide phosphate (NADPH)-dependent reduction of a novel substrate by the enzyme dihydrofolate reductase (DHFR). The system is represented by a coupled quantum mechanical and molecular mechanical (QM/MM) model based on the AM1 semiempirical molecular orbital method for the reacting substrate and NADPH cofactor fragments, the AMBER force field for DHFR, and the TIP3P model for solvent water. The FEP calculations were performed for a number of choices for the QM system. The substrate, 8-methylpterin, was treated quantum mechanically in all the calculations, while the larger cofactor molecule was partitioned into various QM and MM regions with the addition of “link” atoms (F, CH₃, and H). Calculations were also carried out with the entire NADPH molecule treated by QM. The free energies of reaction and the net charges on the NADPH fragments were used to determine the most appropriate QM/MM model. The hydride-ion transfer was also carried out over several FEP pathways, and the QM and QM/MM component free energies thus calculated were found to be state functions (i.e., independent of pathway). A ca. 10 kcal/mol increase in free energy for the hydride-ion transfer with an activation barrier of ca. 30 kcal/mol was calculated. The increase in free energy on the hydride-ion transfer arose largely from the QM/MM component. Analysis of the QM/MM energy components suggests that, although a number of charged residues may contribute to the free energy change through long-range electrostatic interactions, the only interaction that can account for the 10 kcal/mol increase in free energy is the hydrogen bond between the carboxylate side chain of Glu30 (avian DHFR) and the activated (protonated) substrate. © 1998 John Wiley & Sons, Inc. J Comput Chem 19: 977–988, 1998     

Modelling the active site of glyceraldehyde-3 phosphate dehydrogenase with the LSCF formalism

In the framework of a theoretical approach to the relationship between structure and reactivity of the catalytic centers of enzymes, glyceraldehyde-3 phosphate dehydrogenase (GAPDH) has been chosen as a model enzyme. In GAPDH, the proximity of His₁₇₆ increases the reactivity of Cys₁₄₉ at neutral pH; however, its presence alone is not sufficient to explain the reactivity of the catalytic Cys. In order to determine which other interactions play an important role, a study of the geometric and electronic structure of the catalytic site has been made using a hybrid quantum mechanics/molecular mechanics local self-consistent field method. This allows the computation of the electronic properties of amino acid residues in subsystems influenced by other parts of the macromolecule. The quantum subsystem was centered on the Cys₁₄₉ residue of GAPDH. The structures of GAPDH taken from the crystallographic database did not include hydrogen atoms and these had to be added taking into account the fact that, in the active site, His₁₇₆ has three tautomeric forms: δ-His protonated, ε-His protonated and His⁺. The results presented here suggest that the most stable His…Cys system in GAPDH is a strongly hydrogen-bonded Cys₁₄₉ ⁻/His₁₇₆ ⁺ ion pair. Received: 24 March 1998 / Accepted: 3 September 1998 / Published online: 23 November 1998     

Comparative analysis of the applicability of AM1 and CNDO/2 methods for quantitative prediction of the35Cl NQR frequencies of RC-Cl compounds

The³⁵Cl NQR frequencies of a series of RC-Cl compounds were calculated by the AM1 and CNDO/2 methods in the Townes-Dailey approximation. It was shown that neither of these methods can be directly used for the quantitative prediction of NQR frequencies, and their use in the correlation approach is only possible in narrow series. The AM1 method gives better results for saturated compounds.Institute of Organic and Physical Chemistry, Kazan' Scientific Center, Russian Academy of Sciences, 420083 Kazan'. Translated from Izvestiya Akademii Nauk, Seriya Khimicheskaya, No. 5, pp. 1078–1082, May, 1992.