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Results for “Molecular Docking Simulation”

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PubMedDate not supplied

[Optical biosensor study and molecular modeling of interactions between cytochrome P450cam and cytochrome b5].

The formation of complexes of cytochrome P450cam (P450cam) with full-length cytochrome b5 (d-b5) and its tryptic water-soluble fragment (t-b5) was analyzed using a two-channel IAsys+ optical biosensor. It was found that t-b5 can form complexes with P450cam, while d-b5 does not interact with P450cam. The involvement of amine groups of P450cam in the complex formation was demonstrated. The temperature dependence of t-b5(im)/P450cam complex formation was measured. The association rate constant (k(on)) increased with temperature, while the dissociation rate constant (k(off)) practically remained unchanged. It was concluded that hydrophobic interactions play a key role in the complex formation, while electrostatic interactions are significant for complex stabilization. Based on temperature dependence the activation energy, enthalpy and entropy of complex formation were calculated. It was shown that the entropy component plays a key role in t-b5(im)/P450cam interaction. Computer modeling of P450cam/t-b5 and P450cam/d-b5 interactions was carried out. Using the method of molecular docking some hypotheses of protein-protein complexes were advanced and the best ones were selected based on geometric complementarity, calculated binding energy and probability of electron tunneling between proteins. The computer modeling has shown that only P450cam and t-b5 can form the stable complex. These results are in good agreement with the experimental data obtained with the optical biosensor.

Amino Acid Sequence↗

PubMed2003

A novel shape complementarity scoring function for protein-protein docking.

Shape complementarity is the most basic ingredient of the scoring functions for protein-protein docking. Most grid-based docking algorithms use the total number of grid points at the binding interface to quantify shape complementarity. We have developed a novel Pairwise Shape Complementarity (PSC) function that is conceptually simple and rapid to compute. The favorable component of PSC is the total number of atom pairs between the receptor and the ligand within a distance cutoff. When applied to a benchmark of 49 test cases, PSC consistently ranks near-native structures higher and produces more near-native structures than the traditional grid-based function, and the improvement was seen across all prediction levels and in all categories of the benchmark. Without any post-processing or biological information about the binding site except the complementarity-determining region of antibodies, PSC predicts the complex structure correctly for 6 test cases, and ranks at least one near-native structure in the top 20 predictions for 18 test cases. Our docking program ZDOCK has been parallelized and the average computing time is 4 minutes using sixteen IBM SP3 processors. Both ZDOCK and the benchmark are freely available to academic users (http://zlab.bu.edu/~ rong/dock).

Binding Sites↗

PubMed2005

Prediction of novel and analogous folds using fragment assembly and fold recognition.

A number of new and newly improved methods for predicting protein structure developed by the Jones-University College London group were used to make predictions for the CASP6 experiment. Structures were predicted with a combination of fold recognition methods (mGenTHREADER, nFOLD, and THREADER) and a substantially enhanced version of FRAGFOLD, our fragment assembly method. Attempts at automatic domain parsing were made using DomPred and DomSSEA, which are based on a secondary structure parsing algorithm and additionally for DomPred, a simple local sequence alignment scoring function. Disorder prediction was carried out using a new SVM-based version of DISOPRED. Attempts were also made at domain docking and "microdomain" folding in order to build complete chain models for some targets.

Algorithms↗

PubMed2003

Docking studies of matrix metalloproteinase inhibitors: zinc parameter optimization to improve the binding free energy prediction.

Docking of metalloproteinase inhibitors remains a challenge due to the zinc multiple coordination geometries and the lack of appropriate force field parameters to model the metal/ligand interactions. In this study, we explore the docking accuracy and scoring reliability for the docking of matrix metalloproteinase (MMP) inhibitors using AutoDock 3.0. Potential problems associated with zinc ion were investigated by docking 16 matrix metalloproteinase ligands to their crystal structures. A good coordination between the zinc binding group (ZBG) and the zinc was shown to be a prerequisite for the ligand to fit the binding site. A simplex optimization of zinc parameters, including zinc radius, well depth, and zinc charges, was performed utilizing the 14 MMP complexes with good docking. The use of optimized zinc parameters (zinc radius: 0.87 A; well depth: 0.35 kcal/mol; and zinc charges: +0.95 e) shows improvement in both docking accuracy at the zinc binding site and the prediction of binding free energies. Although further improvement in the docking procedure, particularly the scoring function is needed, optimization of zinc parameters provides an efficient way to improve the performance of AutoDock as a drug discovery tool.

Binding Sites↗

PubMedDate not supplied

Improved FlexX docking using FlexS-determined base fragment placement.

We report on a novel hybrid FlexX/FlexS docking approach, whereby the base fragment of the test ligand is chosen by FlexS superposition onto a cocrystallized template ligand and then fed into FlexX for the incremental construction of the final solution. The new approach is tested on the diverse 200 protein-ligand complex dataset that has been previously described for FlexX validation. In total, 62.9% of the complexes can be reproduced at rank 1 by our approach, which compares favorably with 46.9% when using FlexX alone. In addition, we report "cross-docking" experiments in which several receptor structures of complexes with identical proteins have been used for docking all cocrystallized ligands of these complexes. The results show that, in almost all cases, the hybrid approach can acceptably dock a ligand into a foreign receptor structure using a different ligand template, can give solutions where FlexX alone fails, and tends to give solutions that are more accurately positioned.

Algorithms↗

PubMed2006

Residue conservation information for generating near-native structures in protein-protein docking.

MOTIVATION: Protein-protein docking algorithms typically generate large numbers of possible complex structures with only a few of them resembling the native structure. Recently (Duan et al., Protein Sci, 14:316-218, 2005), it was observed that the surface density of conserved residue positions is high at the interface regions of interacting protein surfaces, except for antibody-antigen complexes, where a lesser number of conserved positions than average is observed at the interface regions. Using this observation, we identified putative interacting regions on the surface of interacting partners and significantly improved docking results by assigning top ranks to near-native complex structures. In this paper, we combine the residue conservation information with a widely used shape complementarity algorithm to generate candidate complex structures with a higher percentage of near-native structures (hits). What is new in this work is that the conservation information is used early in the generation stage and not only in the ranking stage of the docking algorithm. This results in a significantly larger number of generated hits and an improved predictive ability in identifying the native structure of protein-protein complexes. RESULTS: We report on results from 48 well-characterized protein complexes, which have enough residue conservation information from the same 59 benchmark complexes used in our previous work. We compute conservation indices of residue positions on the surfaces of interacting proteins using available homologous sequences from UNIPROT and calculate the solvent accessible surface area. We combine this information with shape-complementarity scores to generate candidate protein-protein complex structures. When compared with pure shape-complementarity algorithms, performed by FTDock, our method results in significantly more hits, with the improvement being over 100% in many instances. We demonstrate that residue conservation information is useful not only in refinement and scoring of docking solutions, but also helpful in enrichment of near-native-structures during the generation of candidate geometries of complex structures.

Amino Acid Sequence↗

PubMed2003

Simulating disorder-order transitions in molecular recognition of unstructured proteins: where folding meets binding.

A microscopic study of functional disorder-order folding transitions coupled to binding is performed for the p27 protein, which derives a kinetic advantage from the intrinsically disordered unbound form on binding with the phosphorylated cyclin A-cyclin-dependent kinase 2 (Cdk2) complex. Hierarchy of structural loss during p27 coupled unfolding and unbinding is simulated by using high-temperature Monte Carlo simulations initiated from the crystal structure of the tertiary complex. Subsequent determination of the transition-state ensemble and the proposed atomic picture of the folding mechanism coupled to binding provide a microscopic rationale that reconciles the initiation recruitment of p27 at the cyclin A docking site with the kinetic benefit for a disordered alpha-helix in the unbound form of p27. The emerging structural polarization in the ensemble of unfolding/unbinding trajectories and in the computationally determined transition-state ensemble is not determined by the intrinsic folding preferences of p27 but rather is attributed to the topological requirements of the native intermolecular interface to order beta-hairpin and beta-strand of p27 that could be critical for nucleating rapid folding transition coupled to binding. In agreement with the experimental data, the disorder-order folding transition for p27 is largely determined by the functional requirement to form a specific intermolecular interface that ultimately dictates the folding mechanism and overwhelms any local folding preferences for creating a stable alpha-helix in the p27 structure before overcoming the major free energy barrier.

Models, Molecular↗

PubMed1993

Crystal structure of cleaved bovine antithrombin III at 3.2 A resolution.

The crystal structure of cleaved antithrombin III (ATIII) has been determined to 3.2 A resolution by single isomorphous replacement, real space density modification and phase extension protocols. The heavy-atom sites and the first molecular envelope were determined owing to the molecular replacement solution previously reported and partially refined. Refinement of the two molecules of the asymmetric unit led to a crystallographic R-factor of 0.212 for all reflections between 8.0 and 3.2 A, without inclusion of water molecules. The root-mean-square deviation from ideal values is, respectively, 0.015 A and 3.6 degrees for bond lengths and bond angles. The topology of the molecule closely resembles that of cleaved serpins inhibitors with the two residues forming the reactive bond at opposite ends of the molecule. The most significant difference between ATIII and alpha 1-antitrypsin lies in the 45 residue N-terminal extension in ATIII which contribute to the definition of the heparin binding site. This loop region at the surface of the molecule is held by two disulphide bridges to the protein core and exhibits high temperature factor values. It forms a valley which restrains the possibilities for binding of heparin. Docking of the pentasaccharide unit which represents the minimum fragment of heparin able to bind to ATIII indicates a possible role for arginine 14 in the interaction of heparin and the protein.

Amino Acid Sequence↗

PubMed2006

Structural insights into human 5-lipoxygenase inhibition: combined ligand-based and target-based approach.

The human 5-LOX enzyme and its interaction with competitive inhibitors were investigated by means of a combined ligand-based and target-based approach. First, a pharmacophore model was generated for 16 non redox 5-LOX inhibitors with Catalyst (HipHop module). It includes two hydrophobic groups, an aromatic ring, and two hydrogen bond acceptors. The 3D structure of human 5-LOX was then modeled based on the crystal structure of rabbit 15-LOX, and the binding modes of representative ligands were studied by molecular docking. Confrontation of the docking results with the pharmacophore model allowed the weighting of the pharmacophoric features and the integration of structural information. This led to the proposal of an interaction model inside the 5-LOX active site, consisting of four major and two secondary interaction points: on one hand, two hydrophobic groups, an aromatic ring, and a hydrogen bond acceptor, and, on the other hand, an acidic moiety and an additional hydrogen bond acceptor.

Amino Acid Sequence↗

PubMed2003

Molecular evaluation using in silico protein interaction profiles.

MOTIVATION: To find a correlation between the activities and structures of molecules is one of the most important subjects for molecular evaluation study. Traditional quantitative structure-activity relationship (QSAR) methodologies represent those attempts using physicochemical descriptors. Creating a new molecular description factor based on the results of a computational docking study will add new dimensions to molecular evaluation. RESULTS: We propose a new molecular description factor analysis system called the Comparative Molecular Interaction Profile Analysis (CoMIPA) system in which the AutoDock program is used for docking evaluation of small molecule compound-protein complexes. Interaction energies are calculated, and the data sets obtained are called interaction profiles (IPFs). Using the IPF as a scoring indicator, the system could be a powerful tool to cluster the interacting properties between small molecules and bio macromolecules such as ligand-receptor bindings. Further development of the system will enable us to predict the adverse effects of a drug candidate.

Algorithms↗

PubMed2000

Design and realization of a tailor-made enzyme to modify the molecular recognition of 2-arylpropionic esters by Candida rugosa lipase.

Within a research project aimed at probing the substrate specificity and the enantioselectivity of Candida rugosa lipase (CRL), computer modeling studies of the interactions between CRL and methyl (+/-)-2-(3-benzoylphenyl)propionate (Ketoprofen methyl ester) have been carried out in order to identify which amino acids are essential to the enzyme/substrate interaction. Different binding models of the substrate enantiomers to the active site of CRL were investigated by applying a computational protocol based on molecular docking, conformational analysis, and energy minimization procedures. The structural models of the computer generated complexes between CRL and the substrates enabled us to propose that Phe344 and Phe345, in addition to the residues constituting the catalytic triad and the oxyanion hole, are the amino acids mainly involved in the enzyme-ligand interactions. To test the importance of these residues for the enzymatic activity, site-directed mutagenesis of the selected amino acids has been performed, and the mutated enzymes have been evaluated for their conversion and selectivity capabilities toward different substrates. The experimental results obtained in these biotransformation reactions indicate that Phe344 and especially Phe345 influence CRL activity, supporting the findings of our theoretical simulations.

Base Sequence↗

PubMed2006

Evolutionary computation and multimodal search: a good combination to tackle molecular diversity in the field of peptide design.

The awesome degree of structural diversity accessible in peptide design has created a demand for computational resources that can evaluate a multitude of candidate structures. In our specific case, we translate the peptide design problem to an optimization problem, and use evolutionary computation (EC) in tandem with docking to carry out a combinatorial search. However, the use of EC in huge search spaces with different optima may pose certain drawbacks. For example, EC is prone to focus a search in the first good region found. This is a problem not only because of the undesirable and automatic rejection of potentially good search space regions, but also because the found solution may be extremely difficult to synthesize chemically or may even be a false docking positive. In order to avoid rejecting potentially good solutions and to maximize the molecular diversity of the search, we have implemented evolutionary multimodal search techniques, as well as the molecular diversity metric needed by the multimodal algorithms to measure differences between various regions of the search space.

Algorithms↗

PubMed2006

DNA strand break: structural and electrostatic properties studied by molecular dynamics simulation.

Due to their lethal consequences and a relatively high probability of introduction of repair errors and mutations, single and double strand breaks are among the most important and dangerous DNA lesions. However, the mechanisms of their recognition and repair processes are only poorly known at present. This work defines and analyzes a DNA with single strand break as a template study for future complex analyses of biologically serious double strand break damage and its enzymatic repair mechanisms. Besides a non-damaged DNA serving as a reference system with no surprising results, system with open valences of the atoms at the strand break ends as well as a system with filled valences were simulated. In both cases during the first few nanoseconds the broken ends of strand breaks are significantly exposed to the outside of the molecule. However, with increasing time, the system with single strand break with open valences is partially disrupted. On the contrary, the system with filled valences shows stable conformation with newly created hydrogen bond between the two strand break endings. Moreover, these endings are steadily situated in the inner part of the molecule, thus making the recognition and docking process of a repair enzyme more complicated in the case of filled valences.

Computational Biology↗

PubMed2005

Evaluating the molecular mechanics poisson-boltzmann surface area free energy method using a congeneric series of ligands to p38 MAP kinase.

The recently described molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) method for calculating free energies is applied to a congeneric series of 16 ligands to p38 MAP kinase whose binding constants span approximately 2 orders of magnitude. These compounds have previously been used to test and compare other free energy calculation methods, including thermodynamic integration (TI), OWFEG, ChemScore, PLPScore, and Dock Energy Score. We find that the MM-PBSA performs relatively poorly for this set of ligands, yielding results much inferior to those from TI or OWFEG, inferior to Dock Energy Score, and not appreciably better than ChemScore or PLPScore but at an appreciably larger computational cost than any of these other methods. This suggests that one should be selective in applying the MM-PBSA method and that for systems that are amenable to other free energy approaches, these other approaches may be preferred. We also examine the single simulation approximation for MM-PBSA, whereby the required ligand and protein trajectories are extracted from a single MD simulation rather than two separate MD runs. This assumption, sometimes used to speed the MM-PBSA calculation, is found to yield significantly inferior results with only a moderate net percentage reduction in total simulation time.

Binding Sites↗

PubMedDate not supplied

New scoring functions for virtual screening from molecular dynamics simulations with a quantum-refined force-field (QRFF-MD). Application to cyclin-dependent kinase 2.

A recently introduced new methodology based on ultrashort (50-100 ps) molecular dynamics simulations with a quantum-refined force-field (QRFF-MD) is here evaluated in its ability both to predict protein-ligand binding affinities and to discriminate active compounds from inactive ones. Physically based scoring functions are derived from this approach, and their performance is compared to that of several standard knowledge-based scoring functions. About 40 inhibitors of cyclin-dependent kinase 2 (CDK2) representing a broad chemical diversity were considered. The QRFF-MD method achieves a correlation coefficient, R(2), of 0.55, which is significantly better than that obtained by a number of traditional approaches in virtual screening but only slightly better than that obtained by consensus scoring (R(2) = 0.50). Compounds from the Available Chemical Directory, along with the known active compounds, were docked into the ATP binding site of CDK2 using the program Glide, and the 650 ligands from the top scored poses were considered for a QRFF-MD analysis. Combined with structural information extracted from the simulations, the QRFF-MD methodology results in similar enrichment of known actives compared to consensus scoring. Moreover, a new scoring function is introduced that combines a QRFF-MD based scoring function with consensus scoring, which results in substantial improvement on the enrichment profile.

Computer Simulation↗

PubMed2004

Unsupervised guided docking of covalently bound ligands.

An approach for docking covalently bound ligands in protein enzymes or receptors was implemented in MacDOCK, a similarity-driven docking program based on DOCK 4.0. This approach was tested with a small number of covalent ligand-protein structures, using both native and non-native protein structures. In all cases, MacDOCK was able to generate orientations consistent with the known covalent binding mode of these complexes, with a performance similar to that of other docking programs. This method was also applied to search for known covalent thrombin inhibitors in a medium-sized molecular database (ca. 11,000 compounds). Detection of functional groups suitable for covalent docking was carried out automatically. A significant enrichment in known active molecules in the first 5% of the database was obtained, showing that MacDOCK can be used efficiently for the virtual screening of covalently bound ligands.

Computer Simulation↗

PubMed2003

Crystal structure of an Acyl-ACP dehydrogenase from the FK520 polyketide biosynthetic pathway: insights into extender unit biosynthesis.

Polyketide synthases (PKSs) synthesize the polyketide cores of pharmacologically important natural products such as the immunosuppressants FK520 and FK506. Understanding polyketide biosynthesis at atomic resolution could present new opportunities for chemo-enzymatic synthesis of complex molecules. The crystal structure of FkbI, an enzyme involved in the biosynthesis of the methoxymalonyl extender unit of FK520, was solved to 2.1A with an R(crys) of 24.4%. FkbI has a similar fold to acyl-CoA dehydrogenases. Notwithstanding this similarity, the surface and substrate-binding site of FkbI reveal key differences from other acyl-CoA dehydrogenases, suggesting that FkbI may recognize an acyl-ACP substrate rather than an acyl-CoA substrate. This structural observation coincided the genetic experiment done by Carroll et al. J. Am. Chem. Soc., 124 (2002) 4176. Although an in vitro assay for FkbI remains elusive, the structural basis for the substrate specificity of FkbI is analyzed by a combination of sequence comparison, docking simulations and structural analysis. A biochemical mechanism for the role of FkbI in the biosynthesis of methoxymalonyl-ACP is proposed.

Acyl Coenzyme A↗

PubMed2003

Analysis and optimization of structure-based virtual screening protocols. (3). New methods and old problems in scoring function design.

Scoring function research remains a primary focus of current structure-based virtual screening (SVS) technology development. Here, we present an alternative method for scoring function design that attempts to combine crystallographic structural information with data derived from directly within SVS calculations. The technique utilizes a genetic algorithm (GA) to optimize functions based on binding property data derived from multiple virtual screening calculations. These calculations are undertaken on protein data bank (PDB) complex active sites using ligands of known binding mode in conjunction with "noise" compounds. The advantages of such an approach are that the function does not rely on assay data and that it can potentially use the "noise" binding data to recognize the sub-optimal docking interactions inherent in SVS calculations. Initial efforts in technique exploration using DOCK are presented, with comparisons made to existing DOCK scoring functions. An analysis of the problems inherent to scoring function development is also made, including issues in dataset creation and limitations in descriptor utility when viewed from the perspective of docking mode resolution. The future directions such studies might take are also discussed in detail.

Algorithms↗