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PubMed2003

Effect of local shape modifications of molecular surfaces on rigid-body protein-protein docking.

Geometric complementarity is the most dominant term in protein-protein docking and therefore, a good geometric representation of the molecules, which takes into account the flexibility of surface residues, is desirable. We present a modified geometric representation of the molecular surface that down-weighs the contribution of specified parts of the surface to the complementarity score. We apply it to the mobile ends of the most flexible side chains: lysines, glutamines and arginines (trimming). The new representation systematically reduces the complementarity scores of the false-positive solutions, often more than the scores of the correct solutions, thereby improving significantly our ability to identify nearly correct solutions in rigid-body docking of unbound structures. The effect of trimming lysine residues is larger than trimming of glutamine or arginine residues. It appears to be independent of the conformations of the trimmed residues but depends on the relative abundance of such residues at the interface and on the non-interacting surface. Combining the modified geometric representation with electrostatic complementarity further improves the docking results.

Arginine↗

PubMed2001

DNA repair mechanism by photolyase: electron transfer path from the photolyase catalytic cofactor FADH(-) to DNA thymine dimer.

Photolyase is an enzyme that catalyses photorepair of thymine dimers in UV damaged DNA by electron transfer reaction. The structure of the photolyase/DNA complex is unknown at present. Using crystal structure coordinates of the substrate-free enzyme from E. coli, we have recently built a computer molecular model of a thymine dimer docked to photolyase catalytic site and studied molecular dynamics of the system. In this paper, we present analysis of the electronic coupling and electron transfer pathway between the catalytic cofactor FADH(-) and the pyrimidine dimer by the method of interatomic tunneling currents. Electronic structure is treated in the extended Hückel approximation. The root mean square transfer matrix element is about 6 cm(-1), which is consistent with the experimentally determined rate of transfer. We find that electron transfer mechanism responsible for the repair utilizes an unusual folded conformation of FADH(-) in photolyases, in which the isoalloxazine ring of the flavin and the adenine are in close proximity, and the peculiar features of the docked orientation of the dimer. The tunneling currents show explicitly that despite of the close proximity between the donor and acceptor complexes, the electron transfer mechanism between the flavin and the thymine bases is not direct, but indirect, with the adenine acting as an intermediate. These calculations confirm the previously made conclusion based on an indirect evidence for such mechanism.

Animals↗

PubMed1995

Molecular recognition of the inhibitor AG-1343 by HIV-1 protease: conformationally flexible docking by evolutionary programming.

BACKGROUND: An important prerequisite for computational structure-based drug design is prediction of the structures of ligand-protein complexes that have not yet been experimentally determined by X-ray crystallography or NMR. For this task, docking of rigid ligands is inadequate because it assumes knowledge of the conformation of the bound ligand. Docking of flexible ligands would be desirable, but requires one to search an enormous conformational space. We set out to develop a strategy for flexible docking by combining a simple model of ligand-protein interactions for molecular recognition with an evolutionary programming search technique. RESULTS: We have developed an intermolecular energy function that incorporates steric and hydrogen-bonding terms. The parameters in this function were obtained by docking in three different protein systems. The effectiveness of this method was demonstrated by conformationally flexible docking of the inhibitor AG-1343, a potential new drug against AIDS, into HIV-1 protease. For this molecule, which has nine rotatable bonds, the crystal structure was reproduced within 1.5 A root-mean-square deviation 34 times in 100 simulations, each requiring eight minutes on a Silicon Graphics R4400 workstation. The energy function correctly evaluates the crystal structure as the global energy minimum. CONCLUSIONS: We believe that a solution of the docking problem may be achieved by matching a simple model of molecular recognition with an efficient search procedure. The necessary ingredients of a molecular recognition model include only steric and hydrogen-bond interaction terms. Although these terms are not necessarily sufficient to predict binding affinity, they describe ligand-protein interactions faithfully enough to enable a docking program to predict the structure of the bound ligand. This docking strategy thus provides an important tool for the interdisciplinary field of rational drug design.

Biological Evolution↗

PubMed2005

Computational identification of proteins for selectivity assays.

At the stage of optimization of a chemical series the compounds are normally assayed for binding or inhibition on the target protein as well as on several proteins from a selectivity panel. These proteins are normally identified on the basis of sequence homology to the target protein. Experimental selectivity data are also taken into account if available. Cases when a nonhomologous protein has a significant affinity to the compound series are going to be missed if the selectivity panel is identified by homology. Experimental data is usually either unavailable or limited to a small fraction of proteins that should be considered. We have developed a computational method of identification of selectivity panel proteins. It is based on the evaluation of binding site similarity to the target protein using docking scores of target-selected molecular probes. These probes are obtained by docking a large library of drug-like compounds to the target protein followed by selecting a diverse subset from the best virtual binders. Docking scores of these probes to other proteins measure binding site similarity to the target. Because the method does not require prior knowledge of either affinities or structures of inhibitors for the target, it can be applied to any protein with known 3D structure. Validation of the method includes rediscovery of nonhomologous proteins that bind common ligands: estradiol, tamoxifen, and riboflavin. Given 3D structures, the method can effectively discriminate proteins with similar binding sites from random proteins independent of sequence homology.

Algorithms↗

PubMed2003

Molecular modeling of diastereoisomeric aggregates of l/d ser/histamine amide with 5'-TpTpdC-3'.

Novel nonpeptide serine/histamine amides (1: l-Ser-Hism,2: d-Ser-Hism) with potent DNA cleavage activity were designed. Conformational analysis and docking study were carried out in an attempt to understand the DNA cleavage mechanism of the designed enantiomeric nonpeptides. First, the most stable conformers of the designed amides were obtained from the conformational analysis by random search. Next, the three-dimensional structures of l-Ser-Hism.5'-TpTpdC-3' and d-Ser-Hism.5'-TpTpdC-3' complexes were built using molecular docking techniques. The docked diastereoisomeric aggregates show that both l-Ser-Hism and d-Ser-Hism bind to two neighboring phosphates in the 5'-TpTpdC-3' backbone through H-bonds. This binding mode suggests a possible phosphodiester bond hydrolysis mechanism. In addition, the binding energies of two constructed complexes were also calculated with the Tripos force field. It indicates that the binding ability between l-Ser-Hism and 5'-TpTpdC-3' is stronger than that of d-Ser-Hism, suggesting a stronger DNA cleavage activity of l-Ser-Hism than that of d-Ser-Hism. The results agree with our experimental DNA cleavage assays. Supplementary material is available for this article if you access the article at http://dx.doi.org/10.1007/s00894-002-0114-9. A link in the frame on the left on that page takes you directly to the supplementary material. Figure Docking structures of1 and2 binding with oligonucleotide: l-Ser-Hism.5'-TpTpdC-3'(left), d-Ser-Hism.5'-TpTpdC-3'(right). Hydrogen bonds are shown in dotted lines. Only one strand of the oligonucleotide is shown for clarity

Amides↗

PubMed2004

Identifying the binding mode of a molecular scaffold.

We describe a method for docking of a scaffold-based series and present its advantages over docking of individual ligands, for determining the binding mode of a molecular scaffold in a binding site. The method has been applied to eight different scaffolds of protein kinase inhibitors (PKI). A single analog of each of these eight scaffolds was previously crystallized with different protein kinases. We have used FlexX to dock a set of molecules that share the same scaffold, rather than docking a single molecule. The main mode of binding is determined by the mode of binding of the largest cluster among the docked molecules that share a scaffold. Clustering is based on our 'nearest single neighbor' method [J. Chem. Inf. Comput. Sci., 43 (2003) 208-217]. Additional criteria are applied in those cases in which more than one significant binding mode is found. Using the proposed method, most of the crystallographic binding modes of these scaffolds were reconstructed. Alternative modes, that have not been detected yet by experiments, could also be identified. The method was applied to predict the binding mode of an additional molecular scaffold that was not yet reported and the predicted binding mode has been found to be very similar to experimental results for a closely related scaffold. We suggest that this approach be used as a virtual screening tool for scaffold-based design processes.

Binding Sites↗

PubMed1994

Molecular modeling of the interaction of polyproline-based peptides with the Abl-SH3 domain: rational modification of the interaction.

A molecular model of the interaction of polyproline-rich peptides with the Abl-SH3 domain is proposed, based on docking calculations with the DOCK program coupled with molecular dynamics simulations. Two distinct binding modes of the peptide to the same aromatic-rich region (Tyr10, Phe12, Trp39, Trp50, Tyr55) of the domain were obtained. It is proposed that these two models could represent different binding modes of proline-rich peptides to Src homology region 3 domains. Several peptide mutants were designed to determine whether the two orientations were possible. Analysis of the Kd values and fluorescence emission of these peptides indicate that one of the orientations is more plausible and that residues at position 4 of the peptide interact with the RT loop, being important in modulating the peptide affinity for the Abl-SH3 domain.

Amino Acid Sequence↗

PubMedDate not supplied

CoMFA and docking study of novel estrogen receptor subtype selective ligands.

We present the results from a Comparative Molecular Field Analysis (CoMFA) and docking study of a diverse set of 36 estrogen receptor ligands whose relative binding affinities (RBA) with respect to 17beta-Estradiol were available in both isoforms of the nuclear estrogen receptors (ER alpha, ER beta). Initial CoMFA models exhibited a correlation between the experimental relative binding affinities and the molecular steric and electrostatic fields; ER alpha: r2 = 0.79, q2 = 0.44 ER beta: r2 = 0.93, q2 = 0.63. Addition of the solvation energy of the isolated ligand improved the predictive nature of the ER beta model initially; r2 = 0.96, q2 = 0.70 but upon rescrambling of the data-set and reselecting the training set at random, inclusion of the ligand solvation energy was found to have little effect on the predictive nature of the CoMFA models. The ligands were then docked inside the ligand binding domain (LBD) of both ER alpha and ER beta utilizing the docking program Gold, after-which the program CScore was used to rank the resulting poses. Inclusion of both the Gold and CScore scoring parameters failed to improve the predictive ability of the original CoMFA models. The subtype selectivity expressed as RBA(ER alpha/ER beta) of the test sets was predicted using the most predictive CoMFA models, as illustrated by the cross-validated r2. In each case the most selective ligands were ranked correctly illustrating the utility of this method as a prescreening tool in the development of novel estrogen receptor subtype selective ligands.

Binding Sites↗

PubMed2006

The molecular basis for ligand specificity in a mouse olfactory receptor: a network of functionally important residues.

Sequence differences between members of the mouse olfac-tory receptor MOR42 subfamily (MOR42-3 and MOR42-1) are likely to be the basis for variation in ligand binding preference among these receptors. We investigated the specificity of MOR42-3 for a variety of dicarboxylic acids. We used site-directed mutagenesis, guided by homology modeling and ligand docking studies, to locate functionally important residues. Receptors were expressed in Xenopus oocytes and assayed using high throughput electrophysiology. The importance of the Val-113 residue, located deep within the receptor, was analyzed in the context of interhelical interactions. We also screened additional residues predicted to be involved in ligand binding site, based on comparison of ortholog/paralog pairs from the mouse and human olfactory receptor genomes (Man, O., Gilad, Y., and Lancet, D. (2004) Protein Sci. 13, 240-254). A network of 8 residues in transmembrane domains III, V, and VI was identified. These residues form part of the ligand binding pocket of MOR42-3. C12 dicarboxylic acid did not activate the receptor in our functional assay, yet our docking simulations predicted its binding site in MOR42-3. Binding without activation implied that C12 dicarboxylic acid might act as an antagonist. In our functional assay, C12 dicarboxylic acid did indeed act as an antagonist of MOR42-3, in agreement with molecular docking studies. Our results demonstrate a powerful approach based on the synergy between computational predictions and physiological assays.

Animals↗

PubMed2005

Combinatorial docking approach for structure prediction of large proteins and multi-molecular assemblies.

Protein folding and protein binding are similar processes. In both, structural units combinatorially associate with each other. In the case of folding, we mostly handle relatively small units, building blocks or domains, that are covalently linked. In the case of multi-molecular binding, the subunits are relatively large and are associated only by non-covalent bonds. Experimentally, the difficulty in the determination of the structures of such large assemblies increases with the complex size and the number of components it contains. Computationally, the prediction of the structures of multi-molecular complexes has largely not been addressed, probably owing to the magnitude of the combinatorial complexity of the problem. Current docking algorithms mostly target prediction of pairwise interactions. Here our goal is to predict the structures of multi-unit associations, whether these are chain-connected as in protein folding, or separate disjoint molecules in the assemblies. We assume that the structures of the single units are known, either through experimental determination or modeling. Our aim is to combinatorially assemble these units to predict their structure. To address this problem we have developed CombDock. CombDock is a combinatorial docking algorithm for the structural units assembly problem. Below, we briefly describe the algorithm and present examples of its various applications to folding and to multi-molecular assemblies. To test the robustness of the algorithm, we use inaccurate models of the structural units, derived either from crystal structures of unbound molecules or from modeling of the target sequences. The algorithm has been able to predict near-native arrangements of the input structural units in almost all of the cases, suggesting that a combinatorial approach can overcome the imperfect shape complementarity caused by the inaccuracy of the models. In addition, we further show that through a combinatorial docking strategy it is possible to enhance the predictions of pairwise interactions involved in a multi-molecular assembly.

Algorithms↗

PubMed1995

Molecular modeling studies of the artemisinin (qinghaosu)-hemin interaction: docking between the antimalarial agent and its putative receptor.

Artemisinin (qinghaosu, QHS) is a promising new antimalarial agent that is effective against drug-resistant strains of malaria. The antimalarial activity of this drug appears to be mediated by an interaction of the drug's endoperoxide bridge with intraparasitic hemin. We have carried out a computer-assisted docking of QHS with hemin from various starting configurations and found that, in the most stable docked configuration, the endoperoxide bridge is in close proximity to the hemin iron. In contrast, an inactive analog, deoxyartemisinin (DQHS), docks in a different manner. Further computer analysis of the drug-hemin interaction might aid in the design of new QHS congeners.

Antimalarials↗

PubMed2000

Molecular modeling of G-protein coupled receptor kinase 2: docking and biochemical evaluation of inhibitors.

G-protein coupled receptor kinase 2 (GRK2) regulates the activity of many receptors. Because potent inhibitors of GRK2 are thus far limited to polyanionic compounds like heparin, we searched for new inhibitors with the aid of a molecular model of GRK2. We used the available crystal structure of cAMP dependent protein kinase (cAPK) as a template to construct a 3D homology model of GRK2. Known cAPK and GRK2 inhibitors were docked into the active sites of GRK2 and cAPK using DOCK v3.5. H8 docked into the hydrophobic pocket of the adenosine 5'-triphosphate (ATP) binding site of cAPK, consistent with its known competitive cAPK inhibition relative to ATP. Similarly, 3 of 4 known GRK2 inhibitors docked into the ATP binding pocket of GRK2 with good scores. Screening the Fine Chemicals Directory (FCD, containing the 3D structures of 13,000 compounds) for docking into the active sites of GRK2 identified H8 and the known GRK2 inhibitor trifluoperazine as candidates. Whereas H8 indeed inhibited light-dependent phosphorylation of rhodopsin by GRK2, but with low potency, 3 additional FCD compounds with promising GRK2 scores failed to inhibit GRK2. This result demonstrates limitations of the GRK2 model in predicting activity among diverse chemical structures. Docking suramin, an inhibitor of protein kinase C (not present in FCD) yielded a good fit into the ATP binding site of GRK2 over cAPK. Suramin did inhibit GRK2 with IC50 32 microM (pA26.39 for competitive inhibition of ATP). Suramin congeners with fewer sulfonic acid residues (NF062, NF503 [IC50 14 microM]) or representing half of the suramin molecule (NF520) also inhibited GRK2 as predicted by docking. In conclusion, suramin and analogues are lead compounds in the development of more potent and selective inhibitors of GRK2.

Animals↗

PubMed1997

ESCHER: a new docking procedure applied to the reconstruction of protein tertiary structure.

Evaluation of Surface Complementarity, Hydrogen bonding, and Electrostatic interaction in molecular Recognition (ESCHER) is a new docking procedure consisting of three modules that work in series. The first module evaluates the geometric complementarity and produces a set of rough solutions for the docking problem. The second module identifies molecular collisions within those solutions, and the third evaluates their electrostatic complementarity. We describe the algorithm and its application to the docking of cocrystallized protein domains and unbound components of protein-protein complexes. Furthermore, ESCHER has been applied to the reassociation of secondary and supersecondary structure elements. The possibility of applying a docking method to the problem of protein structure prediction is discussed.

Protein Structure, Secondary↗

PubMed2006

Flexible docking of an amyloid-forming peptide from beta(2)-microglobulin.

Using an all-atom, molecular dynamics-based, flexible docking method, the tertiary and quaternary structures of protofilaments of the "K3" fragment from beta(2)-microglobulin (residues Ser20-Lys41) were predicted at low pH in a continuous mixture of water and 2,2,2-trifluoroethanol (TFE). Tetramers with energies very close to the global minimum were produced with C(alpha) root-mean square deviation values under 4A over 88 residues compared to a recently solved SSNMR structure. The most accurate model distinguishes itself from other low-energy solutions in that it shows high structural similarity to another known fold, the parallel beta-helix, in agreement with models proposed previously by several other groups. The method achieves efficiency without loss of generality or atomic detail by enforcing local symmetry on the individual peptides, rewarding intermolecular contacts, and iteratively building up the protofilaments by successively doubling the number of chains. Solvent effects were included in the model by treating the dielectric constant and surface tension as functions of the TFE concentration. In order to understand the physical basis for the stabilizing effects of TFE, the TFE concentration was varied from 0% to 50% (v/v) and a peak in stability was observed at 16%, where the polar and hydrophobic terms cancel out and close to the experimentally determined value of 20%.

Amyloid↗

PubMed2001

Fragment-Based flexible ligand docking by evolutionary optimization.

A new computational approach for the efficient docking of flexible ligands in a rigid protein is presented. It exploits the binding modes of functional groups determined by an exhaustive search with solvation. The search in ligand conformational space is performed by a genetic algorithm whose scoring function approximates steric effects and intermolecular hydrogen bonds. Ligand conformations generated by the genetic algorithm are docked in the protein binding site by optimizing the fit of their fragments to optimal positions of chemically related functional groups. We show that the use of optimal binding modes of molecular fragments allows to dock known inhibitors with about ten rotatable bonds in the active site of the uncomplexed and complexed conformations of thrombin and HIV-1 protease.

Algorithms↗

PubMed1993

Docking the mitochondrial inhibitor protein IF1 to a membrane receptor different from the F1-ATPase beta subunit.

Monoclonal antibodies reacting with the inhibitor protein (IF1) of the mitochondrial ATPase/ATP synthase complex did not modify the IF1-induced inhibition of soluble F1 ATPase activity. On the contrary, they increased the ATPase activity of inverted electron-transport particles without inducing a significant release of IF1 from these particles. This suggested that IF1 could be linked to a membrane protein when it was not inhibiting the ATPase activity. IF1 antibodies have been used to show that IF1 can bind not only to the beta subunit of F1-ATPase [Klein, G., Satre, M., Dianoux, A. C. & Vignais, P. V. (1981) Biochemistry 20, 1339-1344] but also to a protein present in the inner-mitochondrial membrane. The cross-linking of IF1 to this membrane protein gave a product of M(r) 15000-16000 that migrated differently from IF1 and from the dimer of IF1 using SDS/PAGE. When the cross-linked product was obtained by using a cleavable cross-linking reagent, the complex between IF1 and the docking protein was partly dissociated and free IF1 was recovered. Considering the molecular mass of IF1, this docking protein for IF1 has apparent M(r) 5000-6000. The complex between IF1 and this receptor protein can be detected in low amounts by antibodies against IF1 in the absence of cross-linking reagent. Since this complex remained in the pellet after treatment of the membrane with Triton X-100, it should be a membrane protein. Therefore, IF1 can bind not only to its inhibitory-binding site at the beta subunit of F1, but also to a non inhibitory site which is a membrane protein of approximate M(r) 5000-6000.

Animals↗

PubMed1998

Inactivation of a common epitope responsible for the induction of antibody-dependent enhancement of HIV.

BACKGROUND: The primary antigenic domain responsible for complement-mediated antibody-dependent enhancement (C'-ADE) of HIV and simian immunodeficiency virus resides in the principal immunodominant sequence of the transmembrane protein. OBJECTIVE: To identify whether there are amino-acid residues common to the epitopes of the known enhancing human monoclonal antibodies (MAb), and to provide a structural model for this functional region present on the HIV envelope. Since our model predicts that this region is involved in the association of gp120 with gp41, this association was monitored for each mutant. DESIGN: The binding of enhancing human MAb to point and deletion mutations within the enhancing domain was analyzed by two methods. The first analyzed binding to mutants expressed in COS cells: the second quantified the binding of four enhancing human MAb to each mutant gp160 versus wild-type control by enzyme-linked immunosorbent assay (ELISA). METHODS: Site-directed mutagenesis was used to produce specific deletions and point mutants, which were expressed in COS cells. Binding of MAb 50-69 and V3-loop MAb 5F7 were visualized in the wild-type and each of the mutant constructs by immunohistochemistry. Quantitative evaluation of enhancing human MAb binding to each mutant versus wild-type was performed by ELISA. A model for the enhancing domain and its relationship to gp120 association with gp41 was provided by molecular dynamics and ligand docking methods. RESULTS: All available enhancing human MAb known to bind to the principal immunodominant region of gp41 were unable to bind to deletions involving the disulfide loop, which in our molecular model provided the primary association site between gp120 and gp41. Point mutations in the loop blocked this association, but had a quantitatively smaller effect on the binding of the enhancing human MAb. A conservative W596Y mutation completely blocked the binding of all human MAb, but had no effect on gp120-gp41 association. CONCLUSIONS: A variety of mutations within the primary C'-ADE domain inhibit binding of enhancing human MAb as well as blocking the association of gp120 and gp41. A conservative W596Y mutation blocks binding of all enhancing human MAb with retention of gp120-gp41 association. These data are important to the design of vaccines in which the primary enhancing epitope is disarmed to prevent the subsequent induction of an amnestic response that could lead to viral enhancement of infection. The retention of the gp120-gp41 association is postulated to yield an immunogen similar to natural infection for both subunit and genetic vaccines.

Amino Acid Sequence↗

PubMed2005

Application of the in combo screening approach for the discovery of non-alkaloid acetylcholinesterase inhibitors from Cichorium intybus.

Because of the direct correlation of cholinergic deficit and the severity of dementia, Alzheimer's disease is preferentially treated with acetylcholinesterase (AChE) inhibitors to supplement the acetylcholine level. In this study we focused on non-alkaloid AChE inhibitors from natural sources in order to discover new lead structures. In the course of in vitro extract screening of Tyrolean plants using an enzyme assay with Ellman's reagent, the dichloromethane extract of chicory roots (Cichorium intybus L.) showed a pronounced inhibitory effect on AChE. At a concentration of 1 mg extract/ml an inhibition of 70% was measured. Based on a 3D multi-conformational molecular-structure database consisting of secondary metabolites from C. intybus known from the relevant literature, virtual screening filtering experiments were conducted using both a feature-based pharmacophore model and a docking procedure. Some low molecular weight sesquiterpenoids exhibited distinct interactions with the pharmacophore model. In order to verify the applicability of this computer-aided strategy, an activity-guided fractionation of the chicory root extract was performed, which resulted in the isolation of two sesquiterpene lactones, 8-deoxylactucin and lactucopicrin, showing significant and dose-dependent inhibitory activity on AChE (IC(50) of 308.1 microM [CI(95) 243.9 - 405.3 microM] and 150.3 microM [CI(95) 100.8 - 188.1 microM], respectively). The two isolates were correctly predicted within the virtual screening process which corroborates the potential of the computer-assisted in combo screening approach for the discovery of the anti-cholinesterase compounds from C. intybus.

Acetylcholinesterase↗