A novel method for superimposing molecules and receptor mapping

Superposition of molecules on a three-dimensional computer graphic display is an efficient means to compare three-dimensional molecular structures. Biologically active molecules, which are presumed to bind to the same receptor site, are thought to have common structural features. But, it is the physical and chemical properties arranged spatially through chemical structures that are important for specific binding to a receptor. Therefore, for the purpose of studies on biological activities, molecules should be superposed to those properties, not to the atomic positions as in the traditional methods. We have developed a program system for realizing this new concept. The concept stands on the general perceptions of organic chemists about hydrogen bondings and chemical isosterisms. The 'goodness of fit' values, which are estimated in realtime on the basis of spatial similarity of those properties between molecules, are displayed and updated throughout the superposing process. This program can construct a receptor cavity model and provide with the cavity size and shape, surface electrostatic potentials, hydrogen bonding sites and so on, by using all information supplied by the superposed molecules. This model can be modified by further superposing of another molecule. These constructed models would be of help for rational drug design, when the receptor structures are not yet known.     

惰性化学键活化与重组

惰性化学键的活化与重组是近几年来非常热门的研究领域, 同时这个领域也非常富有挑战性. 本文以麻生明教授为首席的国家重点基础研究发展项目（973项目）“惰性化学键的选择性激活、重组及其控制”为基础, 阐述了惰性碳-杂原子键, 碳-氢键, 碳-碳键, 二氧化碳和氧气小分子四个方面的活化和重组, 介绍了一些催化合成的新方法. 这些新方法在完成惰性化学键活化和重组的同时, 也注重于降低污染, 使用更温和的条件, 提高了原子经济性, 为可持续发展战略提供了强有力的技术支持.     

slate: A method for the superposition of flexible ligands

A novel program for the superposition of flexible molecules, slate, is presented. It uses simulated annealing to minimise the difference between the distance matrices calculated from the hydrogen-bonding and aromatic-ring properties of two ligands. A method for generating a molecular stack using multiple pairwise matches is illustrated. These stacks are used by the program doh to predict the relative positions of receptor atoms that could form hydrogen bonds to two or more ligands in the dataset. The methodology has been applied to ligands binding to dihydrofolate reductase, thermolysin, H₃ histamine receptors, ₂ adrenoceptors and 5-HT_1D receptors. When there are sufficient numbers and diversity of molecules in the dataset, the prediction of receptor-atom positions is applicable to compound design.     

An automated method for predicting the positions of hydrogen-bonding atoms in binding sites

Hydrogen bonds are the most specific, and therefore predictable of the intermolecular interactions involved in ligand–protein binding. Given the structure of a molecule, it is possible to estimate the positions at which complementary hydrogen-bonding atoms could be found. Crystal-survey data are used in the design of a program, HBMAP, that generates a hydrogen-bond map for any given ligand, which contains all the feasible positions at which a complementary atom could be found. On superposition of ligands, the overlapping regions of their maps represent positions of receptor atoms to which each molecule can bind. The certainty of these positions is increased by the incorporation of a larger number and diversity of molecules. In this work, superposition is achieved using the program HBMATCH, which uses simulated annealing to generate the correspondence between points from the hydrogen-bonding maps of the two molecules. Equivalent matches are distinguished on the basis of their steric similarity. The strategy is tested on a number of ligands for which ligand–protein complexes have been solved crystallographically, which allows validation of the techniques. The receptor atom positions of thermolysin are successfully predicted when the correct superposition is obtained.     

The computer program LUDI: A new method for the de novo design of enzyme inhibitors

Summary A new computer program is described, which positions small molecules into clefts of protein structures (e.g. an active site of an enzyme) in such a way that hydrogen bonds can be formed with the enzyme and hydrophobic pockets are filled with hydrophobic groups. The program works in three steps. First it calculates interaction sites, which are discrete positions in space suitable to form hydrogen bonds or to fill a hydrophobic pocket. The interaction sites are derived from distributions of nonbonded contacts generated by a search through the Cambridge Structural Database. An alternative route to generate the interaction sites is the use of rules. The second step is the fit of molecular fragments onto the interaction sites. Currently we use a library of 600 fragments for the fitting. The final step in the present program is the connection of some or all of the fitted fragments to a single molecule. This is done by bridge fragments. Applications are presented for the crystal packing of benzoic acid and the enzymes dihydrofolate reductase and trypsin.     

环双(对-蒽基-对草快)的分子识别与谱学性质

环双(对-蒽基-对草快)是一种新型的缺电子大环仿生主体, 分子识别是其最重要的应用之一. 考察主体对一系列客体分子如水、氨、醇及杂环等的识别能力, 用密度泛函理论(DFT)中的B3LYP/3-21G基组对主客体复合物的结构进行优化. 在B3LYP/6-31G(d)水平上进行单点能计算, 校正后得到复合物的结合能. 用B3LYP/3-21G方法计算13C和3He化学位移. 结果表明, 主体对客体分子的识别主要靠客体上的杂原子与主体上的氢原子之间的氢键进行. 复合物的稳定化能受氢键的数目和距离影响. 氢键的形成导致部分复合物LUMO与HOMO能隙增大, 同时导致与氢键相连的C—H键上C原子的化学位移向低场移动. 复合物的芳香性与其结合能的大小及结合方式有关. 主体的芳香性因其与客体之间的弱相互作用而提高, 但太强的相互作用及客体在主体空腔内都将影响主体的环电流, 从而削弱其芳香性.     

“Crystal” conformations of 2-methyl-2,4-pentanediol: Dipole moment calculations and molecular structure optimizations

The structures of eight symmetrically independent molecules of 2-methyl-2,4-pentanediol (MPD) in six crystal substances are studied based on the data retrieved from the Cambridge Structural Database (CSD). Coordinates of the most part of hydrogen atoms in MPD molecules were not determined experimentally or not presented in CSD, however, O...O distances provide the conclusion about the formation of intramolecular hydrogen bonds in four molecules. To perform quantum chemical calculations the absent hydrogen atoms were added. The choice of H atomic positions in hydroxyl groups are based on the analysis of possible formation of intra- and intermolecular hydrogen bonds by MPD molecules in the respective crystals. The DFT method with the B3PW91 functional and the 6-31G(d,p) basis set is used to carry out for the first time: 1) the calculation of dipole moments and energies for MPD molecules in “crystal” conformations; 2) the optimization of the structure of these molecules with the calculation of dipole moments for the conformations corresponding to the local energy minima. It is found that among the molecules with the experimental geometric parameters one of the conformations without intramolecular hydrogen bonds is most favorable (μ = 0.56 D). As a result of the energy minimization of eight “crystal” conformations in vacuum, five energetically different conformers are obtained. Among them the conformer with the intramolecular hydrogen bond has the lowest energy (μ = 3.53 D). Four variants of the molecular structure correspond to it in the considered crystals, out of which two are R-enantiomers and two S-enantiomers.     

鸟嘌呤与氨基酸残基体系的极化力场

发展了应用于鸟嘌呤G和氨基酸残基体系的浮动电荷力场, 该力场明确定义了孤对电子和键的电荷和位置, 通过电荷随着环境的浮动来体现极化效应; 通过氢键拟合函数k_HB描绘了氢键键能. 应用量子化学方法, 对G与氨基酸残基体系从氢键、 几何结构及电荷分布3个方面展开计算及分析, 并以其为基准, 确定参数发展了适用于G与氨基酸残基氢键体系的ABEEMσπ PFF. 采用3种不同力场模拟目标分子的结构和性质. 模拟结果表明, 发展的ABEEMσπ PFF与量子化学方法具有最好的一致性, 可用于模拟生物大分子体系.     

Quantum similarity superposition algorithm (QSSA): a consistent scheme for molecular alignment and molecular similarity based on quantum chemistry

The use of the molecular quantum similarity overlap measure for molecular alignment is investigated. A new algorithm is presented, the quantum similarity superposition algorithm (QSSA), expressing the relative positions of two molecules in terms of mutual translation in three Cartesian directions and three Euler angles. The quantum similarity overlap is then used to optimize the mutual positions of the molecules. A comparison is made with TGSA, a topogeometrical approach, and the influence of differences on molecular clustering is discussed.     

Influence of N-H...O and C-H...O hydrogen bonds on the 17O NMR tensors in crystalline uracil: computational study

We report a computational study for the 17O NMR tensors (electric field gradient and chemical shielding tensors) in crystalline uracil. We found that N-H...O and C-H...O hydrogen bonds around the uracil molecule in the crystal lattice have quite different influences on the 17O NMR tensors for the two C=O groups. The computed 17O NMR tensors on O4, which is involved in two strong N-H...O hydrogen bonds, show remarkable sensitivity toward the choice of cluster model, whereas the 17O NMR tensors on O2, which is involved in two weak C-H...O hydrogen bonds, show much smaller improvement when the cluster model includes the C-H...O hydrogen bonds. Our results demonstrate that it is important to have accurate hydrogen atom positions in the molecular models used for 17O NMR tensor calculations. In the absence of low-temperature neutron diffraction data, an effective way to generate reliable hydrogen atom positions in the molecular cluster model is to employ partial geometry optimization for hydrogen atom positions using a cluster model that includes all neighboring hydrogen-bonded molecules. Using an optimized seven-molecule model (a total of 84 atoms), we were able to reproduce the experimental 17O NMR tensors to a reasonably good degree of accuracy. However, we also found that the accuracy for the calculated 17O NMR tensors at O2 is not as good as that found for the corresponding tensors at O4. In particular, at the B3LYP/6-311++G(d,p) level of theory, the individual 17O chemical shielding tensor components differ by less than 10 and 30 ppm from the experimental values for O4 and O2, respectively. For the 17O quadrupole coupling constant, the calculated values differ by 0.30 and 0.87 MHz from the experimental values for O4 and O2, respectively.     

A method for fast energy estimation and visualization of protein-ligand interaction

Summary A new computational and graphical method for facilitating ligand-protein docking studies is developed on a three-dimensional computer graphics display. Various physical and chemical properties inside the ligand binding pocket of a receptor protein, whose structure is elucidated by X-ray crystal analysis, are calculated on three-dimensional grid points and are stored in advance. By utilizing those tabulated data, it is possible to estimate the non-bonded and electrostatic interaction energy and the number of possible hydrogen bonds between protein and ligand molecules in real time during an interactive docking operation. The method also provides a comprehensive visualization of the local environment inside the binding pocket.With this method, it becomes easier to find a roughly stable geometry of ligand molecules, and one can therefore make a rapid survey of the binding capability of many drug candidates. The method will be useful for drug design as well as for the examination of protein-ligand interactions.     

Role of hydrogen bonds in protein-DNA recognition: effect of nonplanar amino groups

Amino groups are one of the various types of hydrogen bond donors, abundantly found in protein main chains, protein side chains, and DNA bases. The polar hydrogen atoms of these groups exhibit short ranged, specific, and directional hydrogen bonds, which play a decisive role in the specificity and stability of protein-DNA complexes. To date, planar amino groups are only considered for the analysis of protein-DNA interfacial hydrogen bonds. This assumption regarding hydrogen atom positions possibly failed to establish the expected role of hydrogen bonds in protein-DNA recognition. We have performed ab initio quantum chemical studies on amino acid side chains and DNA bases containing amino groups as well as on specific hydrogen bonded residue pairs selected from high-resolution protein-DNA complex crystal structures. Our results suggest that occurrences of pyramidal amino groups are more probable in comparison with the usually adopted planar geometry. This increases the quality of the existing hydrogen bonds in almost all cases. Further, detailed analysis of protein-DNA interfacial hydrogen bonds in 107 crystal structures using the in-house program "pyrHBfind" indicates that consideration of energetically more preferred nonplanar amino groups improves the geometry of hydrogen bonds and also gives rise to new contacts amounting to nearly 14.5% of the existing interactions. Large improvements have been observed specifically for the amino groups of guanine, which faces the DNA minor groove and thus helps to resolve the problem of insufficient directional contacts observed in many minor groove binding complexes. Apart from guanine, improvement observed for asparagine, glutamine, adenine, or cytosine also indicates that the consideration of nonplanar amino groups leads to a more realistic scenario of hydrogen bonds occurring between protein and DNA residues.     

Theoretical binding affinities and spectroscopy of complexes formed by cyclobis(paraquat-<Emphasis Type="Italic">p</Emphasis>-anthrancene) with some pharmaceutical molecules

Theoretical investigation on the stabilities and spectroscopic properties of the complexes formed by cyciobis(paraquat-p-anthracene) with pharmaceutical molecules were performed using the semi-empirical PM3 and B3LYP/3-21G methods. Based on the B3LYP/3-21G optimized geometries, the energies of the complexes were calculated at B3LYP/6-31G(d) level. The binding energies of the complexes were computed after the correction of basis set superposition error (BSSE). The energy gaps of the complexes are decreased due to the formation of the hydrogen bonds. The stretching vibrations of the C-H bonds adjacent to the hydrogen bonds in the IR spectra of the complexes calculated with PM3 method are red-shifted compared with those of the host. The chemical shifts of α-C and β-C atoms in the complexes calculated at B3LYP/3-21G level are shifted downfield due to the formation of the hydrogen bonds and the electron-withdrawing effect of the nitrogen atoms. The aromaticities of the complexes are improved because of the enlargement of the conjugation system and the overlap of electron cloud based on the nuclear independent chemical shifts (NICS) calculated at B3LYP/3-21G level.     

Density functional studies on hydrogen‐bonded clusters of hydrogen halides and the interaction on halide anions

Density functional theory (DFT) calculations have been performed to study the structures and stability of X^?·(HX)_n=2–5 clusters where X = F, Cl, Br at B3LYP/6‐311++G** level of theory. The presence of halide ions in these clusters disintegrates the hydrogen halide clusters. All the hydrogen halides are then hydrogen bonded to the centrally placed halide ions, thereby forming multiple hydrogen bonds. The interaction energies have been corrected for the basis set superposition error (BSSE) using Boy's counterpoise correction method. Evidence for the destruction of hydrogen bonds in hydrogen halide clusters due to the presence of halide ions is further obtained from topological analysis and natural bond orbital analysis. The chemical hardness and chemical potential have been calculated for all the anion clusters. The above analysis reveals that hydrogen bonding in these systems is not an essentially electrostatic interaction. The nature of the stabilization interactions operative in these multiple hydrogen‐bonded clusters has been explained in terms of many‐body contribution to interaction energies. From these studies, an attempt has been made to understand the nature of the molecular properties resulting from different electronegativities of the halogens. © 2005 Wiley Periodicals, Inc. Int J Quantum Chem, 2005     

Simultaneous Estimation of Two Coupled Hydrogen Bond Geometries from Pairs of Entangled NMR Parameters: The Test Case of 4-Hydroxypyridine Anion

The computational method for estimating the geometry of two coupled hydrogen bonds with geometries close to linear using a pair of spectral NMR parameters was proposed. The method was developed based on the quantum-chemical investigation of 61 complexes with two hydrogen bonds formed by oxygen and nitrogen atoms of the 4-hydroxypyridine anion with OH groups of substituted methanols. The main idea of the method is as follows: from the NMR chemical shifts of nuclei of atoms forming the 4-hydroxylpyridine anion, we select such pairs, whose values can be used for simultaneous determination of the geometry of two hydrogen bonds, despite the fact that every NMR parameter is sensitive to the geometry of each of the hydrogen bonds. For these parameters, two-dimensional maps of dependencies of NMR chemical shifts on interatomic distances in two hydrogen bonds were constructed. It is shown that, in addition to chemical shifts of the nitrogen atom and quaternary carbon, which are experimentally difficult to obtain, chemical shifts of the carbons and protons of the CH groups can be used. The performance of the proposed method was evaluated computationally as well on three additional complexes with substituted alcohols. It was found that, for all considered cases, hydrogen bond geometries estimated using two-dimensional correlations differed from those directly calculated by quantum-chemical methods by not more than 0.04 Å.     

Correct bond order assignment in a molecular framework using integer linear programming with application to molecules where only non-hydrogen atom coordinates are available

We describe a method based on linear programming, for deducing the correct bond orders in small molecules, which only needs the sigma bonds connectivity and atom symbols as input. The procedure checks whether the current structure can be written as a valid Lewis structure by assigning double and triple bonds by translating the octet equations into an integer linear program that is solved by an external solver. The procedure was intensively tested on some ligands from the protein data bank as well as some other exotic molecules, for which first the hydrogen topology is generated by a standard procedure from literature. The most stable Lewis structure is retained for which hydrogen coordinates are generated.     

Calculation of the van der Waals volumes of organic molecules

A new and more precise method is proposed for calculating van der Waals atomic and molecular volumes of organic compounds. The method provides for intersections of three or more spheres at one point of space. Such a possibility is essential for calculating the volumes of sterically overcrowded molecules and of molecules with intramolecular hydrogen bonds. A computer program for IBM PC/AT(XT) is developed. Depending on the atomic environment in the molecule, the average values of the volume increments for atoms C, N, O, H, F, Cl, and S are obtained using the data from the Cambridge Structural Database.N. S. Kurnakov Institute of General and Inorganic Chemistry, Russian Academy of Sciences, Moscow 117071. Translated from Izvestiya Akademii Nauk, Seriya Khimicheskaya, No. 4, pp. 922–931, April, 1992.     

Relationship between the critical points found by the electron localization function and atoms in molecules approaches in adducts with hydrogen bonds

In this work, 11 adducts with hydrogen bonds were studied by using the B3LYP exchange-correlation functional of the Kohn-Sham approach and the M?ller-Plesset second-order perturbation theory MP2. With both approaches, the geometry of each adduct was optimized with the aug-cc-pVTZ basis set. The binding energies of the considered systems, found by the MP2 method, range from 1.2 to 8.3 kcal/mol. By using the atoms in molecules (AIM) analysis and the electron localization function (ELF) we found that the critical points positions characteristic of hydrogen bonds obtained by AIM and ELF are very similar each other. Besides, we found a linear correlation between the critical points positions found by AIM and those obtained by ELF with the B3LYP method and also with the MP2 method. The slope of such a linear relationship was close to 1 and the y-intercept close to 0.     

Density Functional Theory Study of the Interaction between Guanine and Catechin

The interacting patterns and mechanism of the catechin and guanine have been investigated with the density functional theory B3LYP method by 6‐31G* basis set. Fourteen stable structures for the catechin‐guanine complexes have been found which form two hydrogen bonds at least. The results indicate that the complexes are mainly stabilized by the hydrogen bonding interactions. At the same time, the number and strength of hydrogen bond play a co‐determinant parts in the stability of the complexes which can form two or more hydrogen bonds. Theories of atoms in molecules (AIM) and natural bond orbital (NBO) have been adopted to investigate the hydrogen bonds involved in all systems. The interaction energies of all complexes have been corrected for basis set superposition error (BSSE), ranging from ?38.86 to ?14.56 kJ/mol. The results showed that the hydrogen bonding contributes to the interaction energies dominantly. The corresponding bonds stretching motions in all complexes are red‐shifted relative to that of the monomer, which is in agreement with experimental results.