Showing papers on "Docking (molecular) published in 1991"

Protein-protein recognition analyzed by docking simulation.

Abstract: Antibody-lysozyme and protease-inhibitor complexes are reconstituted by docking lysozyme as a rigid body onto the combining site of the antibodies and the inhibitors onto the active site of the proteases. Simplified protein models with one sphere per residue are subjected to simulated annealing using a crude energy function where the attractive component is proportional to the interface area. The procedure finds clusters of orientations in which a steric fit between the two protein components is achieved over a large contact surface. With five out of six complexes, the native structure of the complexes determined by X-ray crystallography is among those retained. Docked complexes are then subjected to conformational energy refinement with full atomic detail. With Fab HyHEL 5 and lysozyme, a native-like complex has the lowest refined energy. It can also be retrieved when starting with the X-ray structure of free lysozyme. However, some non-native complexes cannot be rejected: they form large interfaces, have a large number of H-bonds, and few unpaired polar groups. While these are necessary features of protein-protein recognition, they are not sufficient in determining specificity.

Molecular modelling of protein-carbohydrate interactions. Docking of monosaccharides in the binding site of concanavalin A

Abstract: A general procedure is described for addressing the computer simulation of protein-carbohydrate interactions. First, a molecular mechanical force field capable of performing conformational analysis of oligosaccharides has been derived by the addition of new parameters to the Tripos force field; it is also compatible with the simulation of protein. Second, a docking procedure which allows for a systematic exploration of the orientations and positions of a ligand into a protein cavity has been designed. This so-called 'crankshaft' method uses rotations and variations about/of virtual bonds connecting, via dummy atoms, the ligand to the protein binding site. Third, calculation of the relative stability of protein ligand complexes is performed. This strategy has been applied to search for all favourable interactions occurring between a lectin [concanavalin A (ConA)] and methyl alpha-D-mannopyranoside or methyl alpha-D-glucopyranoside. For each monosaccharide, different stable orientations and positions within the binding site can be distinguished. Among them, one corresponds to very favourable interactions, not only in terms of hydrogen bonding, but also in terms of van der Waals interactions. It corresponds precisely to the binding mode of methyl alpha-D-mannopyranoside into ConA as revealed by the 2.9 A resolution of the crystalline complex (Derewenda et al., 1989). Some implications of the present modelling study with respect to the molecular basis of the specificity of the interaction of lectins with various monosaccharides are presented.

Constructing a molecular model of the interaction between Antithrombin-III and a potent synthetic heparin Analogue.

Abstract: Information about the antithrombin 111-heparin interaction is deduced from the following: (i) structure-activity studies of various synthetic analogues of the antithrombin I11 binding pentasaccharide domain of heparin, which revealed that essential sulfate and carboxylate substituents are located at opposite sides of the pentasaccharide molecule; (ii) studies that designated the heparin-binding amino acid residues of antithrombin 111; (iii) a molecular model of antithrombin 111, constructed on the basis of the crystal structure of a1-antitrypsin. From these studies it could be deduced that both the protein and the carbohydrate display an asymmetric assembly of essential interaction points. Docking trials indicated a single complex in which the interaction points are complementary. The latter complex was optimized by molecular dynamics simulations. The final model reveals, for the first time, how a well-defined region of a sulfated polysaccharide can interact specifically with a complementary binding site on a functional protein.

Molecular dynamics of dopamine at the D2 receptor.

Abstract: A three-dimensional model of the dopamine D2 receptor, assumed to be a target of antipsychotic drug action, was constructed from its amino acid sequence. The model was based on structural similarities within the super-family of guanine nucleotide-binding regulatory (G) protein-coupled neuroreceptors and has seven alpha-helical transmembrane segments that form a central core with a putative ligand-binding site. The space between two residues postulated to be involved in agonist binding, Asp-80 and Asn-390, perfectly accommodated an anti-dopamine molecule. Molecular electrostatic potentials were mainly negative on the synaptic side of the receptor model and around aspartate residues lining the central core and positive in the cytoplasmic domains. The docking of dopamine into a postulated binding site was examined by molecular dynamics simulation. The protonated amino group became oriented toward negatively charged aspartate residues in helix 2 and helix 3, whereas the dopamine molecule fluctuated rapidly between different anti and gauche conformations during the simulation. The receptor model suggests that protonated ligands are attracted to the binding site by electrostatic forces and that protonated agonists may induce conformational changes in the receptor, leading to G-protein activation, by increasing the electrostatic potentials near Asp-80.

Computer-aided active-site-directed modeling of the herpes simplex virus 1 and human thymidine kinase.

Abstract: Thymidine kinase (TK), which is induced by Herpes Simplex Virus 1 (HSV1), plays a key role in the antiviral activity of guanine derivatives such as aciclovir (ACV). In contrast, ACV shows only low affinity to the corresponding host cell enzyme. In order to define the differences in substrate binding of the two enzymes on molecular level, models for the three-dimensional (3-D) structures of the active sites of HSV1-TK and human TK were developed. The reconstruction of the active sites started from primary and secondary structure analysis of various kinases. The results were validated to homologous enzymes with known 3-D structures. The models predict that both enzymes consist of a central core β-sheet structure, connected by loops and α-helices very similar to the overall structure of other nucleotide binding enzymes. The phosphate binding is made up of a highly conserved glycine-rich loop at the N-terminus of the proteins and a conserved region at the C-terminus. The thymidine recognition site was found about 100 amino acids downstream from the phosphate binding loop. The differing substrate specificity of human and HSV1-TK can be explained by amino-acid substitutions in the homologous regions. To achieve a better understanding of the structure of the active site and how the thymidine kinase proteins interact with their substrates, the corresponding complexes of thymidine and dihydroxypropoxyguanine (DHPG) with HSV1 and human TK were built. For the docking of the guanine derivative, the X-ray structure of Elongation Factor Tu (EF-Tu), co-crystallized with guanosine diphosphate, was taken as reference. Fitting of thymidine into the active sites was done with respect to similar interactions found in thymidylate kinase. To complement the analysis of the 3-D structures of the two kinases and the substrate enzyme interactions, site-directed mutagenesis of the thymidine recognition site of HSV1-TK has been undertaken, changing Asp162 in the thymidine recognition site into Asn. First investigations reveal that the enzymatic activity of the mutant protein is destroyed.

Molecular modeling of antibody-antigen complexes between the Brucella abortus O-chain polysaccharide and a specific monoclonal antibody.

Abstract: A molecular model of the binding site of an anti-carbohydrate antibody (YsT9.1) has been developed using computer-assisted modeling techniques and molecular dynamics calculations. Sequence homologies among YsT9.1 and the Fv regions of McPC603, J539 and human Bence--Jones protein REI, all of which have solved crystal structures, provided the basis for the modeling. The groove-type combining site model had a topography which was complementary to low energy conformers of the polysaccharide, a Brucella O-antigen, and the site could be almost completely filled by a pentasaccharide epitope in either of two docking modes. Putative interactions between this epitope and the antibody are consistent with the known structural requirements for binding and lead to the design of oligosaccharide inhibitors that probe the veracity of the modeled docked complex. Ultimately both the Fv model and the docked complex will be compared with independent crystal structures of YsT9.1 Fab with and without pentasaccharide inhibitor, currently at the stage of refinement.

Chapter 29. Receptor Modeling by Distance Geometry

Abstract: Publisher Summary Distance geometry is a general molecular model-building method known for determining the three-dimensional solution structures of peptides, proteins, and nucleic acids from nuclear overhauser effect (NOE) distance measurements. It has also been applied to the models of proteins and receptors and the interaction of small molecules with the receptors. A recently published comprehensive review of distance geometry and its application to receptor modeling emphasizes their distance geometry quantitative structure–activity relationship (QSAR) approaches. This chapter discusses the additional distance geometry approaches that have application in receptor modeling and distance geometry QSAR method, protein structure modeling, drug receptor docking, and pharmacophore modeling using the ensemble approach. Crippen applied distance geometry to the problem of three-dimensional receptor mapping. Ghose and Crippen have reviewed the approach in detail. Ghose and Crippen's method proposed the geometric requirements of the receptor site based on the experimental data of binding affinities of a series of ligands that may be conformationally flexible and may be hypothesized binding modes for each ligand. The result was a low-resolution, three-dimensional model of the receptor binding site, which was described as a series of points in space (site points) that interact with specific ligand atoms or groups of atoms (ligand points). Each ligand point was described by atom-centered physicochemical properties (molar refractivity, hydrophobicity, and partial charge). A specific interaction energy was assigned to each site point—ligand point interaction by a modified quadratic programming optimization procedure—yielding a quantitative prediction of the binding affinity of each ligand to the site model. The chapter discusses Voronoi binding site models. Distance geometry software is now more readily available, along with a steadily increasing number of applications and publications that demonstrate molecular models involving drug–receptor docking, pharmacophore modeling, protein structure prediction, and conformational analysis.