Small-molecule Crystal Structures Research Articles

Discovering H-Bonding Rules in Crystals with Inductive Logic Programming

In the domain of crystal engineering, various schemes have been proposed for the classification of hydrogen bonding (H-bonding) patterns observed in 3D crystal structures. In this study, the aim is to complement these schemes with rules that predict H-bonding in crystals from 2D structural information only. Modern computational power and the advances in inductive logic programming (ILP) can now provide computational chemistry with the opportunity for extracting structure-specific rules from large databases that can be incorporated into expert systems. ILP technology is here applied to H-bonding in crystals to develop a self-extracting expert system utilizing data in the Cambridge Structural Database of small molecule crystal structures. A clear increase in performance was observed when the ILP system DMax was allowed to refer to the local structural environment of the possible H-bond donor/acceptor pairs. This ability distinguishes ILP from more traditional approaches that build rules on the basis of global molecular properties.

Constructing co-crystals with molecular sense and supramolecular sensibility

Themore than 365,000 organic and organometallic small-molecule crystal structures in the Cambridge Structural Database (CSD) are a good source of data for understanding the crystal structures of solvates. It is trivial with the existing search software [1] to find all CSD entries containing a particular solvent, say water, and a survey of the 50most common solvents in the CSD has been published [2]. It might be interesting, however, to know if any of these solvates also exist in an unsolvated form; given a crystal structure of di-isopropylammonium chloride hydrate in the CSD, for example, one could wonder if a crystal structure of di-isopropylammonium chloride itself is present in the database. A computer program was written that for a given solvent molecule finds all pairs of solvated versus unsolvated CSD entries; a list of solvate structures for which no unsolvated form exists in the CSD is also generated. These lists enable us to examine if properties such as the number of hydrogen-bond donors / acceptors or the molecular flexibility influence solvate formation. Results for hydrates will be presented.

Searching the Cambridge Structural Database for solvatedvsunsolvated pairs

The more than 365,000 organic and organometallic small-molecule crystal structures in the Cambridge Structural Database (CSD) are a good source of data for understanding the crystal structures of solvates. It is trivial with the existing search software [1] to find all CSD entries containing a particular solvent, say water, and a survey of the 50 most common solvents in the CSD has been published [2]. It might be interesting, however, to know if any of these solvates also exist in an unsolvated form; given a crystal structure of di-isopropylammonium chloride hydrate in the CSD, for example, one could wonder if a crystal structure of di-isopropylammonium chloride itself is present in the database. A computer program was written that for a given solvent molecule finds all pairs of solvated versus unsolvated CSD entries; a list of solvate structures for which no unsolvated form exists in the CSD is also generated. These lists enable us to examine if properties such as the number of hydrogen-bond donors / acceptors or the molecular flexibility influence solvate formation. Results for hydrates will be presented.

Extended hydrogen bond patterns in small molecule crystal structures: a CSD study

Extended hydrogen bond patterns in small molecule crystal structures: a CSD study

A Comparison of Staphostatin B with Standard Mechanism Serine Protease Inhibitors

Staphostatins are the endogenous, highly specific inhibitors of staphopains, the major secreted cysteine proteases from Staphylococcus aureus. We have previously shown that staphostatins A and B are competitive, active site-directed inhibitors that span the active site clefts of their target proteases in the same orientation as substrates. We now report the crystal structure of staphostatin B in complex with wild-type staphopain B at 1.9 A resolution. In the complex structure, the catalytic residues are found in exactly the positions that would be expected for uncomplexed papain-type proteases. There is robust, continuous density for the staphostatin B binding loop and no indication for cleavage of the peptide bond that comes closest to the active site cysteine of staphopain B. The carbonyl carbon atom C of this peptide bond is 4.1 A away from the active site cysteine sulfur Sgamma atom. The carbonyl oxygen atom O of this peptide bond points away from the putative oxyanion hole and lies almost on a line from the Sgamma atom to the C atom. The arrangement is strikingly similar to the "ionmolecule" arrangement for the complex of papain-type enzymes with their substrates but differs significantly from the arrangement conventionally assumed for the Michaelis complex of papain-type enzymes with their substrates and also from the arrangement that is crystallographically observed for complexes of standard mechanism inhibitors and their target serine proteases.

Orthogonal Multipolar Interactions in Structural Chemistry and Biology

The past few decades of molecular recognition studies have greatly enhanced our knowledge on apolar, ion-dipole, and hydrogen-bonding interactions. However, much less attention has been given to the role that multipolar interactions, in particular those with orthogonal dipolar alignment, play in organizing a crystal lattice or stabilizing complexes involving biological receptors. By using results from database mining, this review attempts to give an overview of types and structural features of these previously rather overlooked interactions. A number of illustrative examples of these interactions found in X-ray crystal structures of small molecules and protein-ligand complexes demonstrate their propensity and thus potential importance for both, chemical and biological molecular recognition processes.

The Solution Structure of [Cu(aq)]2+ and Its Implications for Rack-Induced Bonding in Blue Copper Protein Active Sites

The structure of [Cu(aq)]2+ has been investigated by using full multiple-scattering theoretical (MXAN) analysis of the copper K-edge X-ray absorption (XAS) spectrum and density functional theory (DFT) to test both ideal Td and square-planar four-coordinate, five-coordinate square-pyramidal, and six-coordinate octahedral [Cu(aq)]2+ models. The best fit was an elongated five-coordinate square pyramid with four Cu-O(eq) bonds (2 x 1.98 +/- 0.03 A and 2 x 1.95 +/- 0.03 A) and a long Cu-O(ax) bond (2.35 +/- 0.05 A). The four equatorial ligands were D2d-distorted from the mean equatorial plane by +/-(17 +/- 4) degrees, so that the overall symmetry of [Cu(H2O)5]2+ is C2v. The four-coordinate MXAN fit was nearly as good, but the water ligands (4 x 1.96 +/- 0.02 A) migrated +/-(13 +/- 4) degrees from the mean equatorial plane, making the [Cu(H2O)4]2+ model again D2d-distorted. Spectroscopically calibrated DFT calculations were carried out on the C2v elongate square-pyramidal and D2d-distorted four-coordinate MXAN copper models, providing comparative electronic structures of the experimentally observed geometries. These calculations showed 0.85e spin on Cu(II) and 0.03e electron spin on each of the four equatorial water oxygens. All covalent bonding was restricted to the equatorial plane. In the square-pyramidal model, the electrostatic Cu-O(ax) bond was worth only 96.8 kJ mol(-1), compared to 304.6 kJ mol(-1) for each Cu-O(eq) bond. Both MXAN and DFT showed the potential well of the axial bond to be broad and flat, allowing large low-energy excursions. The irregular geometry and D2d-distorted equatorial ligand set sustained by unconstrained [Cu(H2O)5]2+ warrants caution in drawing conclusions regarding structural preferences from small molecule crystal structures and raises questions about the site-structural basis of the rack-induced bonding hypothesis of blue copper proteins. Further, previously neglected protein folding thermodynamic consequences of the rack-bonding hypothesis indicate an experimental disconfirmation.

C–H⋯O and other weak hydrogen bonds. From crystal engineering to virtual screening

Hydrogen bonds, X-H...A, formed by weak donors (X = C) and acceptors (A = pi system) were generally dismissed as being of little consequence before and even during the 1970s. This situation changed in the early 1980s, and during the two following decades they were implicated as being significant in many small molecule crystal structures, and also in solution. Today, knowledge gained about these interactions is being used to understand the structure of biomolecules with implications for structure based drug design.

Avoiding and detecting errors in X-ray crystal structures of small molecules

Avoiding and detecting errors in X-ray crystal structures of small molecules

Combined use of physicochemical data and small-molecule crystallographic contact propensities to predict interactions in protein binding sites

Knowledge-based methods are a good alternative to force-field-based methods for the analysis of sites of interaction in protein binding cavities. Both the Protein Data Bank (PDB) and the Cambridge Structural Database (CSD) offer a good amount of data on non-covalent interactions. Although different from protein-derived data, small-molecule crystal data from the CSD are worth looking at as they provide a much more abundant and diverse set of intermolecular contacts. CSD data, when properly corrected by use of octanol-water pi values, can be used to predict the type of ligand chemical group most likely to occupy a given position within a protein binding site. Comparison with observed positions of ligand groups shows that the success rates of these predictions vary from 23% to 84%. Often, the group predicted to be most preferred at a given position is similar but not identical to the observed ligand group; if these are considered successes, prediction success rates range from 71% to 94%. Using PDB data, the corresponding rates are 16% to 79%, and 61% to 96%. Specificity of prediction of NH groups is somewhat better when using PDB interaction data, but results of prediction of hydrophobic groups seem worse than those obtained with CSD data. We have analysed the importance of data selection by applying different filters to eliminate unwanted interactions from our knowledge-base. The presence of certain types of interactions can be undesirable if they are unrepresentative of biological situations (contact to solvent molecules in small-molecule crystal structures, secondary crystallographic contacts) or if they are likely to add noise to the data without conveying much new information (long-distance contacts, sparsely-populated data sets). The elimination of solvent contacts was found to have no effect on the prediction of ligand groups in our test set. Both secondary-contact filtering and noise filtering were found to have a clear beneficial effect on predictive ability.

NH…O, OH…O, and CH…O hydrogen bonds in protein–ligand complexes: Strong and weak interactions in molecular recognition

The characteristics of N-H...O, O-H...O, and C-H...O hydrogen bonds are examined in a group of 28 high-resolution crystal structures of protein-ligand complexes from the Protein Data Bank and compared with interactions found in small-molecule crystal structures from the Cambridge Structural Database. It is found that both strong and weak hydrogen bonds are involved in ligand binding. Because of the prevalence of multifurcation, the restrictive geometrical criteria set up for hydrogen bonds in small-molecule crystal structures may need to be relaxed in macromolecular structures. For example, there are definite deviations from linearity for the hydrogen bonds in protein-ligand complexes. The formation of C-H...O hydrogen bonds is influenced by the activation of the C(alpha)-H atoms and by the flexibility of the side-chain atoms. In contrast to small-molecule structures, anticooperative geometries are common in the macromolecular structures studied here, and there is a gradual lengthening as the extent of furcation increases. C-H...O bonds formed by Gly, Phe, and Tyr residues are noteworthy. The numbers of hydrogen bond donors and acceptors agree with Lipinski's "rule of five" that predicts drug-like properties. Hydrogen bonds formed by water are also seen to be relevant in ligand binding. Ligand C-H...O(w) interactions are abundant when compared to N-H...O(w) and O-H...O(w). This suggests that ligands prefer to use their stronger hydrogen bond capabilities for use with the protein residues, leaving the weaker interactions to bind with water. In summary, the interplay between strong and weak interactions in ligand binding possibly leads to a satisfactory enthalpy-entropy balance. The implications of these results to crystallographic refinement and molecular dynamics software are discussed.

Applying databases of small molecule crystal structures to understanding the interactions about biologically relevent metal centres

Applying databases of small molecule crystal structures to understanding the interactions about biologically relevent metal centres

Improved dihedral-angle restraints for protein structure refinement

Because of the relatively low-resolution diffraction of typical protein crystals, structure refinement is usually carried out employing stereochemical restraints to increase the effective number of observations. Well defined values for bond lengths and angles are available from small-molecule crystal structures. Such values do not exist for dihedral angles because of the concern that the strong crystal contacts in small-molecule crystal structures could distort the dihedral angles. This paper examines the dihedral-angle distributions in ultra-high-resolution protein structures (1.2 Å or better) as a means of analysing the population frequencies of dihedral angles in proteins and compares these with the stereochemical restraints currently used in one of the more widely used molecular-dynamics refinement packages,X-PLOR, and its successor,CNS. Discrepancies between the restraints used in these programs and what is actually seen in high-resolution protein structures are examined and an improved set of dihedral-angle restraint parameters are derived from these inspections.

CSDSymmetry: the definitive database of point-group and space-group symmetry relationships in small-molecule crystal structures.

An algorithm that perceives molecular symmetry has been applied to ca. 200,000 entries from the Cambridge Structural Database (CSD). For each molecule, the perceived point group, together with crystallographic properties such as space group, occupied Wyckoff positions and number of residues in the asymmetric unit, have been placed in a relational database, CSDSymmetry, using Microsoft Access software. Database queries can be constructed easily to find occurrences of any combination of molecular or crystallographic attributes, and thereby to answer questions on relative distributions. Some typical example queries are given. The inclusion of CSD reference codes enables direct visualization of search results using the Cambridge Crystallographic Data Centre's three-dimensional structure visualizer, Mercury.

Life-science applications of the Cambridge Structural Database.

Several studies show that the molecular geometries and intermolecular interactions observed in small-molecule crystal structures are relevant to the modelling of in vivo situations, although the influence of crystal packing is sometimes important and should always be borne in mind. Torsional distributions derived from the Cambridge Structural Database (CSD) can be used to map out potential-energy surfaces and thereby help identify experimentally validated conformational minima of molecules with several rotatable bonds. The use of crystallographic data in this way is complementary to in vacuo theoretical calculations since it gives insights into conformational preferences in condensed-phase situations. Crystallographic data also underpin many molecular-fragment libraries and programs for generating three-dimensional models from two-dimensional chemical structures. The modelling of ligand binding to metalloenzymes is assisted by information in the CSD on preferred coordination numbers and geometries. CSD data on intermolecular interactions are useful in structure-based inhibitor design both in indicating how probable a protein-ligand interaction is and what its geometry is likely to be. They can also be used to guide searches for bioisosteric replacements. Crystallographically derived information has contributed to many life-science software applications, including programs for locating binding 'hot spots' on proteins, docking ligands into enzyme active sites, de novo ligand design, molecular superposition and three-dimensional QSAR. Overall, crystallographic data in general, and the CSD in particular, are very significant tools for the rational design of biologically active molecules.

The Cambridge Structural Database: a quarter of a million crystal structures and rising.

The Cambridge Structural Database (CSD) now contains data for more than a quarter of a million small-molecule crystal structures. The information content of the CSD, together with methods for data acquisition, processing and validation, are summarized, with particular emphasis on the chemical information added by CSD editors. Nearly 80% of new structural data arrives electronically, mostly in CIF format, and the CCDC acts as the official crystal structure data depository for 51 major journals. The CCDC now maintains both a CIF archive (more than 73,000 CIFs dating from 1996), as well as the distributed binary CSD archive; the availability of data in both archives is discussed. A statistical survey of the CSD is also presented and projections concerning future accession rates indicate that the CSD will contain at least 500,000 crystal structures by the year 2010.

Quantum Mechanics Studies of the Intrinsic Conformation of Trehalose

To resolve controversies over the intrinsic shape of the disaccharide α,α-trehalose and the magnitude of solvent effects, energy surfaces have been computed at different levels of molecular orbital and density functional theory. All quantum mechanical (QM) levels agree that the gauche linkage conformations observed by experimental crystallographic and solution studies are 5−7 kcal/mol lower in energy than that of the trans shape. This is quite different than the findings of the two most recent classical force field studies. In those projects, the trans shape was preferred by 3.3 kcal/mol, and it was inferred that a strong solvent effect was responsible for the gauche experimental conformations. In the QM work, a strong solvent effect is not needed to explain the preference for the gauche form because the trans shapes already have higher energy. A QM continuum model of aqueous solvation has only small effects on the torsional energy surface. The best rationalization of 24 values of the linkage torsion angles from small-molecule crystal structures is provided by HF/6-311++G**//B3LYP/6-31G* theory, a level that under-predicts the strength of hydrogen bonds.

The crystal structure of the α-cellobiose·2 NaI·2 H 2O complex in the context of related structures and conformational analysis

The crystal structure of β- d-glucopyranosyl-(1→4)-α- d-glucopyranose (α-cellobiose) in a complex with water and NaI was determined with Mo K α radiation at 150 K to R=0.027. The space group is P2 1 and unit cell dimensions are a=9.0188, b=12.2536, c=10.9016 Å, β=97.162°. There are no direct hydrogen bonds among cellobiose molecules, and the usual intramolecular hydrogen bond between O-3H and O-5′ is replaced by a bridge involving Na +, O-3, O-5′, and O-6′. Both Na + have sixfold coordination. One I − accepts six donor hydroxyl groups and three CH ⋯I − hydrogen bonds. The other accepts three hydroxyls, one Na +, and five CH ⋯I − hydrogen bonds. Linkage torsion angles φ O-5 and ψ C-5 are −73.6 and −105.3°, respectively ( φ H=47.1° and ψ H=14.6°), probably induced by the Na + bridge. This conformation is in a separate cluster in φ, ψ space from most similar linkages. Both C-6OH and C-6′OH are gg, while the C-6′OH groups from molecules not in the cluster have gt conformations. Hybrid molecular mechanics/quantum mechanics calculations show <1.2 kcal/mol strain for any of the small-molecule structures. Extrapolation of the NaI cellobiose geometry to a cellulose molecule gives a left-handed helix with 2.9 residues per turn. The energy map and small-molecule crystal structures imply that cellulose helices having 2.5 and 3.0 residues per turn are left-handed.

Database research in crystal engineering

The Cambridge Structural Database is a storehouse of over 250 000 small-molecule organic and organometallic crystal structures. Statistical analysis of structural data provides a better understanding of the nature of hydrogen bonds and intermolecular interactions and facilitates in the identification of frequently occurring interaction patterns and supramolecular synthons. With an enhanced knowledge of hydrogen bond synthons in crystals, novel strategies may be designed for the self-assembly of supramolecular architectures from multi-functional molecules. The twin phenomena of polymorphism and pseudopolymorphism have been studied by extracting information on molecular conformations and solvent inclusion from the database. The approach geometry of hydrogen bond donors to various functional groups derived from small-molecule crystal structures is used as a model in structure-based drug design and pharmacophore mapping. Thus, the implications of crystal engineering today go far beyond organic and metal–organic crystal design into supramolecular materials, nanotechnology, ligand–protein binding and crystal structure prediction. This Highlight surveys the importance of database research in some of these areas.

Small molecule crystallography in drug design.

Crystal structures of small molecules (i.e. isolated ligands) are a source of valuable structural information helpful in the process of drug design (pharmacophore model elaborations, 3D QSAR, docking, and de novo design). Indeed, structural data obtained from small molecules crystallography can approach ligand-receptor binding by providing unique structural features both about the conformation (internal geometry) of the ligand (s) and about the intermolecular interaction potentially occurring within the active site of a target (enzyme/receptor). Small molecule crystal structure databases can also be used in three dimensional search to identify new drug candidates. Future development in small molecule crystallography (e.g. powder diffraction) should also provide original solutions to complex problems related to polymorphism.