Modeling temporary anions in density functional theory: calculation of the Fukui function

Two approaches are investigated for modeling electron densities of temporary anions in density functional theory (DFT). Both rely on an artificial binding of the excess electron, in one case by a compact basis set and in the other by a potential wall. The key feature of the calculations is that the degree of binding is controlled in both cases by knowledge of the negative electron affinity of the corresponding neutral, approximated in terms of DFT local functional frontier orbital eigenvalues and vertical ionization potential, A=-(epsilon(LUMO)+epsilon(HOMO))-I. To illustrate the two approaches, Fukui functions for nucleophilic attack are determined in four molecules with increasingly negative electron affinities. They yield very similar results, which are notably different to those determined without artificial electron binding. The use of a potential wall has the attractive feature that large, diffuse basis sets can be used, avoiding the need for a compact basis, tailored to a particular molecule.     

Hydration in drug design. 2. Influence of local site surface shape on water binding

Summary If water molecules are strongly bound at a protein-ligand interface, they are unlikely to be displaced during ligand binding. Such water molecules can change the shape of the ligand binding site and thus affect strategies for drug design. To understand the nature of water binding, and factors influencing it, water molecules at the ligand binding sites of 26 high-resolution protein-ligand complexes have been examined here. Water molecules bound in deep grooves and cavities between the protein and the ligand are located in the indentations on the protein-site surface, but not in the indentations on the ligand surface. The majority of the water molecules bound in deep indentations on the protein-site surface make multiple polar contacts with the protein surface. This may indicate a strong binding of water molecules in deep indentations on protein-site surfaces. The local shape of the site surface may influence the binding of water molecules that mediate protein-ligand interactions.     

Designed Synthesis of a Highly Conjugated Hexaethynylbenzene‐Based Host for Supramolecular Architectures

The construction of efficient synthetic functional receptors with tunable cavities, and the self‐organization of guest molecules within these cavities through noncovalent interactions can be challenging. Here we have prepared a double‐cavity molecular cup based on hexaethynylbenzene that possesses a highly π‐conjugated interior for the binding of electron‐rich guests. X‐ray crystallography, NMR spectroscopy, UV/Vis spectroscopy, fluorescent spectroscopy, cyclic voltammetry, and SEM were used to investigate the structures and the binding behaviors. The results indicated that the binding of a guest in one cavity would affect the binding of the same or another guest in the other cavity. The effect of electron transfer in this system suggests ample opportunities for tuning the optical and electronic properties of the molecular cup and the encapsulated guest. The encapsulation of different guests would also lead to different aggregate nanostructures, which is a new way to tune their supramolecular architectures.     

Mapping protein pockets through their potential small-molecule binding volumes: QSCD applied to biological protein structures

Previously we demonstrated a method, Quantized Surface Complementarity Diversity (QSCD), of defining molecular diversity by measuring shape and functional complementarity of molecules to a basis set of theoretical target surfaces [Wintner E.A. and Moallemi C.C., J. Med. Chem., 43 (2000) 1993]. In this paper we demonstrate a method of mapping actual protein pockets to the same basis set of theoretical target surfaces, thereby allowing categorization of protein pockets by their properties of shape and functionality. The key step in the mapping is a `dissection' algorithm that breaks any protein pocket into a set of potential small molecule binding volumes. It is these binding volumes that are mapped to the basis set of theoretical target surfaces, thus measuring a protein pocket not as a single surface but as a collection of molecular recognition environments.     

Geometries and binding energies of small beryllium clusters using various levels of approximations for exchange and correlation: a comparative study

Electronic structure and geometries of small (n≦4) neutral, singly, and doubly ionized clusters of beryllium atoms have been studied using ab initio quantum chemical and local density techniques. In the quantum chemical method the exchange potential is treated exactly in the Hartree-Fock scheme while the correlation correction is incorporated through perturbative procedure. In the density functional approach the exchange and correlation potentials are treated in the local spin density approximation. To facilitate an unambiguous comparison between these methods we have used the same basis functions and numerical procedures. All the investigations yield nearly identical geometries. However, the binding energies using these methods can vary by as much as 2 eV and this variation is comparable to what one obtains using different basis functions.     

The functional domains of dopamine transporter for cocaine analog, CFT binding

Cocaine analogue, CFT (2beta-carbomethoxy-3beta-(4-fluorophenyl) tropane) binding to dopamine transporter (DAT) in different species is quite heterogeneous. CFT is scarcely detected in bovine DAT whereas it is conspicuous in humans. To examine the structural basis for this functional discrepancy, we analyzed transporter chimeras of these two DATs. The CFT binding activities are avid in all of the chimeric DATs of which both of the 3rd and the 6-8th transmembrane domain (TM) are composed of human DAT sequences. On the contrary, CFT binding activities were scarcely detected if either or both of two regions are replaced with bovine sequences. These findings indicate that the CFT binding absolutely requires human DAT sequences, at least, in the regions encompassing the 3rd and 6-8th transmembrane domain (TM), and that these regions might contribute to form the 3-dimensional pocket for CFT binding.     

Functional group placement in protein binding sites: a comparison of GRID and MCSS

One approach to combinatorial ligand design begins by determining optimal locations (i.e., local potential energy minima) for functional groups in the binding site of a target macromolecule. MCSS and GRID are two methods, based on significantly different algorithms, which are used for this purpose. A comparison of the two methods for the same functional groups is reported. Calculations were performed for nonpolar and polar functional groups in the internal hydrophobic pocket of the poliovirus capsid protein, and on the binding surface of the src SH3 domain. The two approaches are shown to agree qualitatively; i.e., the global characteristics of the functional group maps generated by MCSS and GRID are similar. However, there are significant differences in the relative interaction energies of the two sets of minima, a consequence of the different functional form used to evaluate polar interactions (electrostatics and hydrogen bonding) in the two methods. The single sphere representation used by GRID affords only positional information, supplemented by the identification of hydrogen bonding interactions. By contrast, the multi-atom representation of most MCSS groups yields in both positional and orientational information. The two methods are most similar for small functional groups, while for larger functional groups MCSS yields results consistent with GRID but superior in detail. These results are in accord with the somewhat different purposes for which the two methods were developed. GRID has been used mainly to introduce functionalities at specific positions in lead compounds, in which case the orientation is predetermined by the structure of the latter. The orientational information provided by MCSS is important for its use in the de novo design of large, multi-functional ligands, as well as for improving lead compounds.     

Combination of computational methods,adsorption isotherms and selectivity tests for the conception of a mixed non-covalent–semi-covalent molecularly imprinted polymer of vanillin

A novel molecularly imprinted polymer (MIP) for vanillin was prepared by photo initiated polymerization in dichloromethane using a mixed semi-covalent and non-covalent imprinting strategy. Taking polymerisable syringaldehyde as “dummy” template, acrylamide was chosen as functional monomer on B3LYP/6-31+G(d,p) density functional theory computational method basis with counterpoise. The binding parameters for the recognition of vanillin on imprinted polymers were studied with three different isotherm models (Langmuir, bi-Langmuir and Langmuir–Freundlich) and compared. The results indicate an heterogeneity of binding sites. It was found and proved by DFT calculations that the specific binding of vanillin in the cavities is due to non-covalent interactions of the template with the hydroxyphenyl- and the amide-moieties. The binding geometry of vanillin in the MIP cavity was also modelled. The obtained MIP is highly specific for vanillin (with an imprinting factor of 7.4) and was successfully applied to the extraction of vanillin from vanilla pods, red wine spike with vanillin, natural and artificial vanilla sugar with a recovery of 80%.     

Identification of isolated cavity features within molecular dynamics simulated chromatographic surfaces

Highly ordered morphological features were characterized for molecular dynamics simulated alkyl-modified silica models that represent chromatographic materials with enhanced shape recognition capability. Deep cavities (8-10A wide) within the alkyl chains were identified for C18 polymeric models corresponding to shape-selective RPLC stationary phases. The all-trans conformational distal-end segments of these isolated cavities averaged over a 100 ps simulation time interval were observed to increase (up to 15 A) in models with an increase in both surface coverage and corresponding shape selectivity. Similar-structure cavities with significant alkyl chain ordered regions (>11A) were isolated from two independent C18 models (differing in bonding chemistry, density and temperature) that represent highly shape-selective materials. The size and depth of these ordered regions increased (up to 28 A) for the extended-length C30 alkyl phase models. These initial results offer a physical representation of alkyl-modified surfaces that may facilitate the identification of potential molecular features that may be involved in the shape-selective retentive processes, as well as illustrating the potential for such computational techniques to predict the molecular recognition capabilities of novel analyte-specific sorbents.     

光接枝表面修饰法制备牛血红蛋白的分子印迹微球

聚苯乙烯球载体表面经引发转移终止剂修饰后, 采用光接枝表面印迹方法制备了以牛血红蛋白(BHb)为模板分子、丙烯酰胺为功能单体和N,N′-亚甲基双丙烯酰胺为交联剂的分子印迹聚合物微球(MIP). 进一步采用红外光谱(IR)、扫描电子显微镜(SEM)和元素分析对聚合物微球进行了表征, 证实了载体表面成功地接枝了分子印迹层, 并研究了其吸附性能和分子识别选择性能. 结果表明, 采用光接枝表面修饰法制备的分子印迹微球对模板分子有着很好的吸附容量和识别选择性.     

Why not consider a spherical protein? Implications of backbone hydrogen bonding for protein structure and function

The intrinsic ability of protein structures to exhibit the geometric features required for molecular function in the absence of evolution is examined in the context of three systems: the reference set of real, single domain protein structures, a library of computationally generated, compact homopolypeptides, artificial structures with protein-like secondary structural elements, and quasi-spherical random proteins packed at the same density as proteins but lacking backbone secondary structure and hydrogen bonding. Without any evolutionary selection, the library of artificial structures has similar backbone hydrogen bonding, global shape, surface to volume ratio and statistically significant structural matches to real protein global structures. Moreover, these artificial structures have native like ligand binding cavities, and a tiny subset has interfacial geometries consistent with native-like protein-protein interactions and DNA binding. In contrast, the quasi-spherical random proteins, being devoid of secondary structure, have a lower surface to volume ratio and lack ligand binding pockets and intermolecular interaction interfaces. Surprisingly, these quasi-spherical random proteins exhibit protein like distributions of virtual bond angles and almost all have a statistically significant structural match to real protein structures. This implies that it is local chain stiffness, even without backbone hydrogen bonding, and compactness that give rise to the likely completeness of the library solved single domain protein structures. These studies also suggest that the packing of secondary structural elements generates the requisite geometry for intermolecular binding. Thus, backbone hydrogen bonding plays an important role not only in protein structure but also in protein function. Such ability to bind biological molecules is an inherent feature of protein structure; if combined with appropriate protein sequences, it could provide the non-zero background probability for low-level function that evolution requires for selection to occur.     

Block copolymer-directed metal nanoparticle morphogenesis and organization

Advances in the nanoscale design of polymeric, “soft” materials and of metallic, “hard” materials can converge at the “interfaces” to form hybrid nanomaterials with interesting features. Novel optical, magnetic, electronic, and catalytic properties are conferred by metal nanoparticles, depending on their morphology (size and shape), surface properties, and long-range organization. We review here the utilization of block copolymers for the controlled synthesis and stabilization of metal nanoparticles. Solvated block copolymers can provide nanoscale environments of varying and tunable shape, dimensions, mobility, local polarity, concentration, and reactivity. In particular, block copolymers containing poly(ethylene oxide) can exhibit multiple functions on the basis of their organization at the intra-polymer level (i.e., crown ether-like cavities that bind and reduce metal ions), and at the supramolecular level (surface-adsorbed micelles, and ordered arrays of micelles). These block copolymers can thus initiate metal nanoparticle formation, and control the nanoparticle size and shape. The physically adsorbed block copolymers, which can be subsequently removed or exchanged with other functional ligands, stabilize the nanoparticles and can facilitate their integration into diverse processes and products. Block copolymers can be further useful in promoting long-range nanoparticle organization. Several studies have elucidated the nanoparticle synthesis and stabilization mechanism, optimized the conditions for different outcomes, extended the ranges of materials obtained and applications impacted, and generalized the scope of this functional polymer-based nanoparticle synthesis methodology.     

丙烷分子的价轨道(2b2)电子的动量分布测量

电子动量谱学（EMS）是在原子、分子和固体物理中研究电子结构的一种强有力的工具，它基于运动学条件完全确定的（e，2e）碰撞电离反应[1-3]．本文报告用高分辨电子动量谱仪首次测量得到丙烷门3H8）分子的价轨道电子（252）的动量分布·丙烷（C3Hs）价轨道电子的动量分布实验是     

Total energies of molecules with the local density functional approximation and gaussian basis sets

Total energies of small molecules were calculated with a local density functional (LDF) approximation within the LCAO MO SCF scheme. The local spin density functional (LSD) of Gunnarsson and Lundqvist was used. The basis sets used are of contracted gaussian type which allow comparison of LSD with Hartree-Fock (HF) results. The program for calculation of the LSD term was incorporated into the standard ab initio package. The LSD binding energies were in better agreement with experiment than those from HF.     

Rational design based on bioactive conformation analysis of pyrimidinylbenzoates as acetohydroxyacid synthase inhibitors by integrating molecular docking, CoMFA, CoMSIA, and DFT calculations

Pyrimidinylthiobenzoates constitute an important kind of herbicides targeting acetohydroxyacid synthase (AHAS, EC 2.2.1.6), which catalyze the first common step in branched-chain amino acid biosynthesis. Due to the symmetry of 4,6-dimethoxypyrimidyl, there are two kinds of conformation of pyrimidinylthiobenzoates: one's phenyl is left-extending (named conformation-L); the other's phenyl is right-extending (named conformation-R). On the basis of the assumption that 3D quantitative structure-activity relationship (QSAR) models derived from the bioactive conformation should give the best result, a strategy of density-functional-theory-based 3D-QSAR was proposed to identify the bioactive conformation of pyrimidinylthiobenzoates by integrating the techniques of molecular docking, comparative molecular field analysis (CoMFA), comparative molecular similarity indices analysis (CoMSIA), and density functional theory calculation. The combination of three criteria of q2, r2, and r2pred obtained from CoMFA and CoMSIA analyses clearly indicated that conformation-R rather than conformation-L might be the bioactive conformation for pyrimidinylthiobenzoates. A further comparison between the two binding modes indicated that pyrimidinylthiobenzoates and sulfonylureas have very similar binding sites, such as Trp586, Arg380, and Pro192. However, Lys251 formed H bonds with sulfonylureas rather than pyrimidinylthiobenzoates. In addition, the orientation of phenyl groups of the two classes of compounds in the binding pocket were revealed to be opposite, which explained why the mutation of Pro192 displayed different sensitivity to sulfonylureas and pyrimidinylthiobenzoates. On the basis of the understanding of interactions between pyrimidinyl-thiobenzoates and AHAS, we designed and synthesized six 8-(4,6-dimethoxypyrimidin-2-yloxy)-4-methylphthalazin-1-one derivatives according to the 3D-QSAR models. The excellent correlation between the tested Ki values against wild-type A. thaliana acetohydroxyacid synthase and the predicted IC50 values demonstrated the high reliability of the established 3D-QSAR models. To our knowledge, this is the first report highlighting the binding mode of herbicidal pyrimidinylthiobenzoates, which consisted of the reported results of herbicide resistance.     

Molecular docking using the molecular lipophilicity potential as hydrophobic descriptor: impact on GOLD docking performance

GOLD is a molecular docking software widely used in drug design. In the initial steps of docking, it creates a list of hydrophobic fitting points inside protein cavities that steer the positioning of ligand hydrophobic moieties. These points are generated based on the Lennard-Jones potential between a carbon probe and each atom of the residues delimitating the binding site. To thoroughly describe hydrophobic regions in protein pockets and properly guide ligand hydrophobic moieties toward favorable areas, an in-house tool, the MLP filter, was developed and herein applied. This strategy only retains GOLD hydrophobic fitting points that match the rigorous definition of hydrophobicity given by the molecular lipophilicity potential (MLP), a molecular interaction field that relies on an atomic fragmental system based on 1-octanol/water experimental partition coefficients (log P(oct)). MLP computations in the binding sites of crystallographic protein structures revealed that a significant number of points considered hydrophobic by GOLD were actually polar according to the MLP definition of hydrophobicity. To examine the impact of this new tool, ligand-protein complexes from the Astex Diverse Set and the PDB bind core database were redocked with and without the use of the MLP filter. Reliable docking results were obtained by using the MLP filter that increased the quality of docking in nonpolar cavities and outperformed the standard GOLD docking approach.     

Product bound structures of the soluble methane monooxygenase hydroxylase from Methylococcus capsulatus (Bath): protein motion in the alpha-subunit

The soluble methane monooxygenase hydroxylase (MMOH) alpha-subunit contains a series of cavities that delineate the route of substrate entrance to and product egress from the buried carboxylate-bridged diiron center. The presence of discrete cavities is a major structural difference between MMOH, which can hydroxylate methane, and toluene/o-xylene monooxygenase hydroxylase (ToMOH), which cannot. To understand better the functions of the cavities and to investigate how an enzyme designed for methane hydroxylation can also accommodate larger substrates such as octane, methylcubane, and trans-1-methyl-2-phenylcyclopropane, MMOH crystals were soaked with an assortment of different alcohols and their X-ray structures were solved to 1.8-2.4 A resolution. The product analogues localize to cavities 1-3 and delineate a path of product exit and/or substrate entrance from the active site to the surface of the protein. The binding of the alcohols to a position bridging the two iron atoms in cavity 1 extends and validates previous crystallographic, spectroscopic, and computational work indicating this site to be where substrates are hydroxylated and products form. The presence of these alcohols induces perturbations in the amino acid side-chain gates linking pairs of cavities, allowing for the formation of a channel similar to one observed in ToMOH. Upon binding of 6-bromohexan-1-ol, the pi helix formed by residues 202-211 in helix E of the alpha-subunit is extended through residue 216, changing the orientations of several amino acid residues in the active site cavity. This remarkable secondary structure rearrangement in the four-helix bundle has several mechanistic implications for substrate accommodation and the function of the effector protein, MMOB.