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PubMed1997

Molecular docking to ensembles of protein structures.

Until recently, applications of molecular docking assumed that the macromolecular receptor exists in a single, rigid conformation. However, structural studies involving different ligands bound to the same target biomolecule frequently reveal modest but significant conformational changes in the target. In this paper, two related methods for molecular docking are described that utilize information on conformational variability from ensembles of experimental receptor structures. One method combines the information into an "energy-weighted average" of the interaction energy between a ligand and each receptor structure. The other method performs the averaging on a structural level, producing a "geometry-weighted average" of the inter-molecular force field score used in DOCK 3.5. Both methods have been applied in docking small molecules to ensembles of crystal and solution structures, and we show that experimentally determined binding orientations and computed energies of known ligands can be reproduced accurately. The use of composite grids, when conformationally different protein structures are available, yields an improvement in computational speed for database searches in proportion to the number of structures.

Computer Simulation↗
PubMed1997

Development and validation of a genetic algorithm for flexible docking.

Prediction of small molecule binding modes to macromolecules of known three-dimensional structure is a problem of paramount importance in rational drug design (the "docking" problem). We report the development and validation of the program GOLD (Genetic Optimisation for Ligand Docking). GOLD is an automated ligand docking program that uses a genetic algorithm to explore the full range of ligand conformational flexibility with partial flexibility of the protein, and satisfies the fundamental requirement that the ligand must displace loosely bound water on binding. Numerous enhancements and modifications have been applied to the original technique resulting in a substantial increase in the reliability and the applicability of the algorithm. The advanced algorithm has been tested on a dataset of 100 complexes extracted from the Brookhaven Protein DataBank. When used to dock the ligand back into the binding site, GOLD achieved a 71% success rate in identifying the experimental binding mode.

Algorithms↗
PubMed1998

Rapid refinement of protein interfaces incorporating solvation: application to the docking problem.

A computationally tractable strategy has been developed to refine protein-protein interfaces that models the effects of side-chain conformational change, solvation and limited rigid-body movement of the subunits. The proteins are described at the atomic level by a multiple copy representation of side-chains modelled according to a rotamer library on a fixed peptide backbone. The surrounding solvent environment is described by "soft" sphere Langevin dipoles for water that interact with the protein via electrostatic, van der Waals and field-dependent hydrophobic terms. Energy refinement is based on a two-step process in which (1) a probability-based conformational matrix of the protein side-chains is refined iteratively by a mean field method. A side-chain interacts with the protein backbone and the probability-weighted average of the surrounding protein side-chains and solvent molecules. The resultant protein conformations then undergo (2) rigid-body energy minimization to relax the protein interface. Steps (1) and (2) are repeated until convergence of the interaction energy. The influence of refinement on side-chain conformation starting from unbound conformations found improvement in the RMSD of side-chains in the interface of protease-inhibitor complexes, and shows that the method leads to an improvement in interface geometry. In terms of discriminating between docked structures, the refinement was applied to two classes of protein-protein complex: five protease-protein inhibitor and four antibody-antigen complexes. A large number of putative docked complexes have already been generated for the test systems using our rigid-body docking program, FTDOCK. They include geometries that closely resemble the crystal complex, and therefore act as a test for the refinement procedure. In the protease-inhibitors, geometries that resemble the crystal complex are ranked in the top four solutions for four out of five systems when solvation is included in the energy function, against a background of between 26 and 364 complexes in the data set. The results for the antibody-antigen complexes are not as encouraging, with only two of the four systems showing discrimination. It would appear that these results reflect the somewhat different binding mechanism dominant in the two types of protein-protein complex. Binding in the protease-inhibitors appears to be "lock and key" in nature. The fixed backbone and mobile side-chain representation provide a good model for binding. Movements in the backbone geometry of antigens on binding represent an "induced-fit" and provides more of a challenge for the model. Given the limitations of the conformational sampling, the ability of the energy function to discriminate between native and non-native states is encouraging. Development of the approach to include greater conformational sampling could lead to a more general solution to the protein docking problem.

Animals↗
PubMed2000

Automated docking of ligands to antibodies: methods and applications.

Many approaches to studying protein-ligand interactions by computational docking are currently available. Given the structures of a protein and a ligand, the ultimate goal of all docking methods is to predict the structure of the resulting complex. This requires a suitable representation of molecular structures and properties, search algorithms to efficiently scan the configuration space for favorable interaction geometries, and accurate scoring functions to evaluate and rank the generated orientations. For many of the available methods, tests on experimentally known antibody-antigen or antibody-hapten complexes have appeared in the literature. In addition, some of them have been used in predictive studies on antibody-ligand interactions to provide structural insights where adequate experimental information is missing. The AutoDock program is presented as example of a method for flexibly docking ligands to antibodies. Applying parameters of the second-generation AMBER force field, three antibody-hapten complexes (AN02, DB3, NC6.8) are used as new test cases to analyze the ability of the method to reproduce experimental findings. The X-ray structures could be reconstituted and the corresponding solutions were ranked with best energy score in all cases. Docking to the free instead of the complexed NC6.8 structure indicated the limits of the rigid protein treatment, although fairly good guesses about the location of the binding site and the contact residues could still be obtained if conformational flexibility was allowed at least in the ligand.

Animals↗
PubMed1994

Prediction of the binding sites of huperzine A in acetylcholinesterase by docking studies.

We have performed docking studies with the SYSDOC program on acetylcholinesterase (AChE) to predict the binding sites in AChE of huperzine A (HA), which is a potent and selective, reversible inhibitor of AChE. The unique aspects of our docking studies include the following: (i) Molecular flexibility of the guest and the host is taken into account, which permits both to change their conformations upon binding. (ii) The binding energy is evaluated by a sum of energies of steric, electrostatic and hydrogen bonding interactions. In the energy calculation no grid approximation is used, and all hydrogen atoms of the system are treated explicitly. (iii) The energy of cation-pi interactions between the guest and the host, which is important in the binding of AChE, is included in the calculated binding energy. (iv) Docking is performed in all regions of the host's binding cavity. Based on our docking studies and the pharmacological results reported for HA and its analogs, we predict that HA binds to the bottom of the binding cavity of AChE (the gorge) with its ammonium group interacting with Trp84, Phe330, Glu199 and Asp72 (catalytic site) and to the opening of the gorge with its ammonium group partially interacting with Trp279 (peripheral site). At the catalytic site, three partially overlapping subsites of HA were identified which might provide a dynamic view of binding of HA to the catalytic site.

Acetylcholinesterase↗
PubMed1996

Distributed automated docking of flexible ligands to proteins: parallel applications of AutoDock 2.4.

AutoDock 2.4 predicts the bound conformations of a small, flexible ligand to a nonflexible macromolecular target of known structure. The technique combines simulated annealing for conformation searching with a rapid grid-based method of energy evaluation based on the AMBER force field. AutoDock has been optimized in performance without sacrificing accuracy; it incorporates many enhancements and additions, including an intuitive interface. We have developed a set of tools for launching and analyzing many independent docking jobs in parallel on a heterogeneous network of UNIX-based workstations. This paper describes the current release, and the results of a suite of diverse test systems. We also present the results of a systematic investigation into the effects of varying simulated-annealing parameters on molecular docking. We show that even for ligands with a large number of degrees of freedom, root-mean-square deviations of less than 1 A from the crystallographic conformation are obtained for the lowest-energy dockings, although fewer dockings find the crystallographic conformation when there are more degrees of freedom.

Azepines↗
PubMed1996

Validation of the use of intermolecular NOE constraints for obtaining docked structures of protein-ligand complexes.

The use of intermolecular NOEs for docking a small ligand molecule into its target protein has been investigated with the aim of determining the effectiveness and methodology of this type of NOE docking calculation. A high-resolution X-ray structure of a protein-ligand complex has been used to simulate loose distance constraints of varying degrees of quality, typical of those estimated from experimental NOE intensities. These simulated data were used to examine the effect of the number, distribution and representation of the experimental constraints on the precision and accuracy of the calculated structures. A standard simulated annealing protocol was used, as well as a more novel method based on rigid-body dynamics. The results showed some analogies with those from similar studies on complete protein NMR structure determinations, but it was found that more constraints per torsion angle are required to define docked structures of similar quality. The effectiveness of different NOE-constraint averaging methods was explored and the benefits of using 'R-6 averaging' rather than 'centre averaging' with small sets of NOE constraints were shown. The starting protein structure used in docking calculations was obtained from previous X-ray or NMR structure studies on a related complex. The effects on the calculated conformations of introducing structural differences into the binding site of the initial protein structure were also considered.

Binding Sites↗
PubMed2006

Homology modeling and molecular docking study of translationally controlled tumor protein and artemisinin.

Translationally controlled tumor protein (TCTP), also known as histamine releasing factor (HRF), is found abundantly in different eukaryotic cell types. The sequence homology of TCTP between different species is very high, belonging to the MSS4/DSS4 superfamily of proteins. TCTP is involved in both cell growth and human late allergy reaction, as well as having a calcium binding property; however, its primary biological functions remain to be clearly elucidated. In regard to many possible functions, the TCTP of Plasmodium falciparum (Pf) is known to bind with an antimalarial agent, artemisinin, which is activated by heme. It is assumed that the endoperoxide-bridge of artemisinin is opened up by heme to form a free radical, which then eventually alkylates, probably to the Cys14 of PfTCTP. Study of the docking of artemisinin with heme, and subsequently with PfTCTP, was carried out to verify the above hypothesis on the basis of structural interactions. The three dimensional (3D) structure of PfTCTP was built by homology modeling, using the NMR structure of the TCTP of Schizosaccharomyces pombe as a template. The quality of the model was examined based on its secondary structure and biological function, as well as with the use of structure evaluating programs. The interactions between artemisinin, heme and PfTCTP were then studied using the docking program, FlexiDock. The center of the peroxide bond of artemisinin and the Fe of heme were docked within a short distance of 2.6A, implying the strong possibility of an interaction between the two molecules, as proposed. When the activated form of artemisinin was docked on the PfTCTP, the C4-radical of the drug faced towards the sulfur of Cys14 within a distance of 2.48A, again suggesting the possibility of alkylation having occurred. These results confirm the proposed mechanism of the antimalarial effect of artemisinin, which will provide a reliable method for establishing the mechanism of its biological activity using a molecular modeling study.

Antimalarials↗
PubMed2003

Binding site characteristics in structure-based virtual screening: evaluation of current docking tools.

Two new docking programs FRED (OpenEye Scientific Software) and Glide (Schrödinger, Inc.) in combination with various scoring functions implemented in these programs have been evaluated against a variety of seven protein targets (cyclooxygenase-2, estrogen receptor, p38 MAP kinase, gyrase B, thrombin, gelatinase A, neuraminidase) in order to assess their accuracy in virtual screening. Sets of known inhibitors were added to and ranked relative to a random library of drug-like compounds. Performance was compared in terms of enrichment factors and CPU time consumption. Results and specific features of the two new tools are discussed and compared to previously published results using FlexX (Tripos, Inc.) as a docking engine. In addition, general criteria for the selection of docking algorithms and scoring functions based on binding-site characteristics of specific protein targets are proposed. Figure Enrichment factors obtained with FlexX, Glide and FRED docking engines in combination with different scoring functions for seven selected targets with highly variable binding sites

Algorithms↗
PubMed2006

Investigation of the binding mode of (-)-meptazinol and bis-meptazinol derivatives on acetylcholinesterase using a molecular docking method.

Molecular docking has been performed to investigate the binding mode of (-)-meptazinol (MEP) with acetylcholinesterase (AChE) and to screen bis-meptazinol (bis-MEP) derivatives for preferable synthetic candidates virtually. A reliable and practical docking method for investigation of AChE ligands was established by the comparison of two widely used docking programs, FlexX and GOLD. In our hands, we had more luck using GOLD than FlexX in reproducing the experimental poses of known ligands (RMSD<1.5 A). GOLD fitness values of known ligands were also in good agreement with their activities. In the present GOLD docking protocol, (-)-MEP seemed to bind with the enzyme catalytic site in an open-gate conformation through strong hydrophobic interactions and a hydrogen bond. Virtual screening of a potential candidate compound library suggested that the most promising 15 bis-MEP derivatives on the list were mainly derived from (-)-MEP with conformations of (S,S) and (SR,RS) and with a 2- to 7-carbon linkage. Although there are still no biological results to confirm the predictive power of this method, the current study could provide an alternate tool for structural optimization of (-)-MEP as new AChE inhibitors. [Figure: see text].

Acetylcholinesterase↗
PubMed2006

Reverse-docking study of the TADDOL-catalyzed asymmetric hetero-Diels-Alder reaction.

The reverse-docking of a TADDOL catalyst to rigid transition-state (TS) representations of an asymmetric hetero-Diels-Alder reaction is described. The resulting docking poses represent a simplified geometric model of the TS for the catalyzed reaction. The conformational space of the catalyst in proximity to the catalyst-free TS models is sampled stochastically and the energetically favored poses are subjected to a clustering procedure to highlight structural attributes compatible with organocatalysis. Each pose is scored and ranked based on its molecular-mechanics docking energy. The reverse-docking procedure reveals a clear energetic trend in favor of the experimentally preferred product enantiomers. Analysis of the best poses suggests a geometric model that is consistent with principles of molecular recognition, catalysis, and experimental data.

Catalysis↗
PubMed2006

Protein farnesyltransferase: flexible docking studies on inhibitors using computational modeling.

Using MacroModel, peptide, peptidomimetic and non-peptidomimetic inhibitors of the zinc metalloenzyme, farnesyltransferase (FTase), were docked into the enzyme binding site. Inhibitor flexibility, farnesyl pyrophosphate substrate flexibility, and partial protein flexibility were taken into account in these docking studies. In addition to CVFM and CVIM, as well as our own inhibitors FTI-276 and FTI-2148, we have docked other farnesyltransferase inhibitors (FTIs) including Zarnestra, which presently is in advanced clinical trials. The AMBER* force field was employed, augmented with parameters that were derived for zinc. A single binding site model that was derived from the crystal structure of CVFM complexed with farnesyltransferase and farnesylpyrophosphate was used for these studies. The docking results using the lowest energy structure from the simulation, or one of the lowest energy structures, were generally in excellent agreement with the X-ray structures. One of the most important findings of this study is that numerous alternative conformations for the methionine side chain can be accommodated by the enzyme suggesting that the methionine pocket can tolerate groups larger than methionine at the C-terminus of the tetrapeptide and suggesting alternative locations for the placement of side chains that may improve potency.

Alkyl and Aryl Transferases↗
PubMed1992

Docking by least-squares fitting of molecular surface patterns.

Molecular surfaces are fitted to each other by a new solution to the problem of docking a ligand into the active site of a protein molecule. The procedure constructs patterns of points on the surfaces and superimposes them upon each other using a least-squares best-fit algorithm. This brings the surfaces into contact and provides a direct measure of their local complementarity. The search over the ligand surface produces a large number of dockings, of which a small fraction having the best complementarity and the least steric hindrance are evaluated for electrostatic interaction energy. When applied to molecules taken from crystallographically observed complexes, this procedure consistently assigns the lowest electrostatic energies to correct dockings. On independently determined structures, the ability of the method to discern correct dockings depends on how much conformational difference there is between the free and complexed forms of the molecules. The procedure is found to be fast enough on contemporary workstation computers to permit many conformations to be considered, and tolerant enough to make rather coarse bond dihedral sampling a practicable way to overcome the problem of structural flexibility.

Binding Sites↗
PubMed1996

Heteroligation of a mouse monoclonal IgE antibody (La2) with small molecules, analysed by computer-aided automated docking.

A mouse monoclonal anti-TNP IgE antibody (IgE-La2) was screened by a competitive-binding ELISA with a random pool of over 2000 small molecules, mostly drugs, drug derivatives and metabolites. Thirteen of these (naproxene, beta-carboxy-chi-naphthol, oxolinic acid, hymecromone, 8-aminoquinoline, beta-naphthylamine, chi-nitrilo-cinnamic acid, 1,5-diaminonaphthaline, prolonium iodide, diaspirin, 3,4,5-trimethoxy-cinnamic acid, cycrimine, hemimellitic acid) were found to bind as strongly, or stronger, to the antibody as the immunizing hapten. We have used a Monte Carlo search technique for simulated docking of the DNP and non-DNP ligands to a model of the Fv region of IgE(La2). The validity of structural predictions made by the AutoDock program were tested on IgG(ANO2), the three-dimensional structure of which had been obtained previously by X-ray crystallography and 2D-NMR. The rms differences between the experimentally determined and auto-docked complexes in the energetically most favored binding modes were 0.31-0.44 A. Evaluation of structures of IgE(La2)-ligand complexes [including 2,4-dinitrophenol (DNP), 16 DNP amino acids, and the 13 non-DNP ligands listed above] obtained by computer-aided automated docking, suggested the existence of two subsites within an approximately 12 x 18 A2 groove extending between the H and L CDRs. Some of the ligands (DNP-Glu, 8-aminoquinoline, prolonium-I, beta-naphthylamine) were found to bind exclusively to subsite 1, others (DNP-Ala, chi-nitrilo-cinnamic acid, hemimellitic acid, beta-carboxy-chi-naphthol) to subsite 2. The majority of DNP amino acids and other ligands (oxolinic acid, 3,4,5-trimethoxy-cinnamic acid, diaspirin, [R]-cycrimine) were found to occupy an overlapping area including subsites 1 and 2, while some of the compounds (DNP-Asn, DNP-Pro, hymecromone, 1,5-naphthylenediamine) were predicted to interact with either of these subsites with comparable probabilities. When all of the docked La2-ligand complexes were taken into account, five tyrosine residues (H33, L32, L91, L92, L96) were found to provide the majority (53.4%) of all observed contact points. Thus, a multitude of interactions with aromatic residues, and a combinatorial type of interaction within the binding region, seem to be the major factors to explain the mechanism of heteroligation by IgE(La2).

Amino Acid Sequence↗
PubMed1995

Docked granules, the exocytic burst, and the need for ATP hydrolysis in endocrine cells.

Ca(2+)-triggered exocytosis was studied in single rat melanotrophs and bovine chromaffin cells by capacitance measurements. Sustained exocytosis required MgATP, but even in the absence of MgATP, Ca2+ could trigger exocytosis of 2700 granules in a typical melanotroph and of 840 granules in a chromaffin cell. Granules undergoing ATP-independent exocytosis were similar in number to those appearing docked to the plasmalemma in quickly frozen unfixed sections (3300 in a melanotroph and 830 in a chromaffin cell). Most exocytosis required tens of seconds, but a small pool of granules was released in tens of milliseconds. Evidently, only a small subset of docked granules is rapidly releasable. We suggest that, temporally, the last ATP-dependent step in exocytosis is closely associated with docking and that docked granules reach fusion competence only after subsequent steps.

Adenosine Triphosphate↗
PubMed2004

Influence of stereoisomer of dispiro-1,2,4,5-tetraoxanes on their binding mode with heme and on antimalarial activity: molecular docking studies.

Based on the fact that different isomers may exhibit substantial distinct activities, quantum chemical calculations and automated molecular docking simulations were carried out for 13 dispiro-1,2,4,5-tetraoxane compounds, which experimentally exist as a mixture of several isomers, to elucidate the most probable isomer(s) responsible for their antimalarial activity. The results indicate significant effects of stereoisomer on the binding mode and the activity. Moreover, the antimalarial potency of each compound can be described by the docking results. Compounds 1, 2, 4, 5, 7, and 9 have the most probable isomers coordinate suitably with heme iron and hence they have high activities while the most probable isomer in compounds 3 and 8 could not bind appropriately to heme yielding only moderate activities. On the other hand, the steric hindrance in compounds 11-13 prevents an approach of heme iron to peroxide bonds resulting in a devoid of antimalarial activity. However, compounds 6 and 10 with isopropyl substituents exhibit a different docking character, which is possibly caused by a limitation in molecular flexibility of the available docking technique. Our results can be used as a guideline for stereochemical control in synthesis process to improve drug's potency.

Animals↗
PubMed2004

Functional consequences of a MAPK docking site on human FcgammaRIIb.

Type IIb Fcgamma receptors (FcgammaRIIb) have a major role in regulating B cell activation. Upon its co-aggregation with the B cell receptors (BCR) via immune complexes FcgammaRIIb become phosphorylated on tyrosine within its immunoreceptor tyrosine based inhibitory motif (ITIM) and in turn recruit protein- and inositol phosphatases, inhibiting thereby signal transduction. The intracellular domain of the human FcgammaRIIb has a membrane proximal motif that is very similar to those of MAPK docking site in MAPK-interacting molecules. Additionally, in contrast to the mouse, a serine residue is located next to this motif that is a potential phosphorylation site for Ser/Thr kinases. Our aim was to study the role of the putative MAPK docking motif on FcgammaRIIb mediated function. We report here that MAPKs bind to FcgammaRIIb affinity purified from the detergent extracts of anti-IgM activated and BCR-FcgammaRIIb co-clustered B cells. We detected extracellular signal regulated kinase (ERK) activity in FcgammaRIIb immunoprecipitates and identified the bound proteins as 85, 44 and 42kDa ERKs by Western blots. Active ERKs bound to the synthetic peptide representing the putative docking site of FcgammaRIIb on a Ser/Thr phosphatase dependent manner. The FcgammaRIIb-associated ERKs may phosphorylate the membrane proximal serine of the receptor. We examined the consequences of serine phosphorylation by comparing the proteins that interact with synthetic peptides comprising the combined sequences of the MAPK docking site and the ITIM either in phosphorylated or in non-phosphorylated forms. The results indicate that phosphorylation on serine modifies the binding of Lyn to FcgammaRIIb, thus might negatively regulate phosphorylation of ITIM.

Amino Acid Motifs↗
PubMed2004

Identification of protein-protein interaction sites from docking energy landscapes.

Protein recognition is one of the most challenging and intriguing problems in structural biology. Despite all the available structural, sequence and biophysical information about protein-protein complexes, the physico-chemical patterns, if any, that make a protein surface likely to be involved in protein-protein interactions, remain elusive. Here, we apply protein docking simulations and analysis of the interaction energy landscapes to identify protein-protein interaction sites. The new protocol for global docking based on multi-start global energy optimization of an all-atom model of the ligand, with detailed receptor potentials and atomic solvation parameters optimized in a training set of 24 complexes, explores the conformational space around the whole receptor without restrictions. The ensembles of the rigid-body docking solutions generated by the simulations were subsequently used to project the docking energy landscapes onto the protein surfaces. We found that highly populated low-energy regions consistently corresponded to actual binding sites. The procedure was validated on a test set of 21 known protein-protein complexes not used in the training set. As much as 81% of the predicted high-propensity patch residues were located correctly in the native interfaces. This approach can guide the design of mutations on the surfaces of proteins, provide geometrical details of a possible interaction, and help to annotate protein surfaces in structural proteomics.

Binding Sites↗