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Results for “Molecular Docking Simulation”

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PubMed1999

Modeling helix-turn-helix protein-induced DNA bending with knowledge-based distance restraints.

A crucial element of many gene functions is protein-induced DNA bending. Computer-generated models of such bending have generally been derived by using a presumed bending angle for DNA. Here we describe a knowledge-based docking strategy for modeling the structure of bent DNA recognized by a major groove-inserting alpha-helix of proteins with a helix-turn-helix (HTH) motif. The method encompasses a series of molecular mechanics and dynamics simulations and incorporates two experimentally derived distance restraints: one between the recognition helix and DNA, the other between respective sites of protein and DNA involved in chemical modification-enabled nuclease scissions. During simulation, a DNA initially placed at a distance was "steered" by these restraints to dock with the binding protein and bends. Three prototype systems of dimerized HTH DNA binding were examined: the catabolite gene activator protein (CAP), the phage 434 repressor (Rep), and the factor for inversion stimulation (Fis). For CAP-DNA and Rep-DNA, the root mean square differences between model and x-ray structures in nonhydrogen atoms of the DNA core domain were 2.5 A and 1.6 A, respectively. An experimental structure of Fis-DNA is not yet available, but the predicted asymmetrical bending and the bending angle agree with results from a recent biochemical analysis.

Base Sequence↗

PubMed2005

Modeling protein recognition of carbohydrates.

We have a limited understanding of the details of molecular recognition of carbohydrates by proteins, which is critical to a multitude of biological processes. Furthermore, carbohydrate-modifying proteins such as glycosyl hydrolases and phosphorylases are of growing importance as potential drug targets. Interactions between proteins and carbohydrates have complex thermodynamics, and in general the specific positioning of only a few hydroxyl groups determines their binding affinities. A thorough understanding of both carbohydrate and protein structures is thus essential to predict these interactions. An atomic-level view of carbohydrate recognition through structures of carbohydrate-active enzymes complexed with transition-state inhibitors reveals some of the distinctive molecular features unique to protein-carbohydrate complexes. However, the inherent flexibility of carbohydrates and their often water-mediated hydrogen bonding to proteins makes simulation of their complexes difficult. Nonetheless, recent developments such as the parameterization of specific force fields and docking scoring functions have greatly improved our ability to predict protein-carbohydrate interactions. We review protein-carbohydrate complexes having defined molecular requirements for specific carbohydrate recognition by proteins, providing an overview of the different computational techniques available to model them.

Acarbose↗

PubMed2001

Design and synthesis of a dimeric derivative of RK-682 with increased inhibitory activity against VHR, a dual-specificity ERK phosphatase: implications for the molecular mechanism of the inhibition.

BACKGROUND: VHR is a dual-specificity phosphatase, which dephosphorylates activated ERK1/2 and weakens the ERK signaling cascade in mammalian cells. A selective inhibitor is expected to be useful for revealing the physiological function of VHR. RESULTS: First, we investigated the molecular mechanism of VHR inhibition by a known natural product, RK-682. Kinetic analysis indicated that inhibition was competitive toward the substrate, and two molecules of RK-682 were required to inhibit one molecule of VHR. Based on the structure-activity relationships for VHR inhibition by RK-682 derivatives, we constructed a binding model using molecular dynamics calculation. Based on this model, we designed and synthesized a novel dimeric derivative. As expected, the dimeric derivative showed increased inhibition of VHR, supporting our proposed mechanism of VHR inhibition by RK-682. CONCLUSION: We have developed a novel inhibitor of VHR based on the results of kinetic analysis and docking simulation.

Dimerization↗

PubMed2000

Construction of a 3D model of oligopeptidase B, a potential processing enzyme in prokaryotes.

A three dimensional structural model of oligopeptidase B (OpB) was constructed by homology modeling. High resolution X-ray structure of prolyl oligopeptidase (PEP), the only protein with sequential and functional homology was used as a template. Initial models of OpB were built by the MODELLER and were analysed by the PROCHECK programs. The best quality model was chosen for further refinement by two different techniques--either constrained molecular dynamics simulations or simulated annealing calculations starting from 500 K. The overall quality of each of the refined models was evaluated and the simulated annealing procedure found to be more effective. The refined model was analysed by different protein analysis programs including PROCHECK for the evaluation of the Ramachandran plot quality, PROSA for testing interaction energies and WHATIF for the calculation of packing quality. This structure was found to be satisfactory and also stable at room temperature as demonstrated by a 300 ps long unconstrained molecular dynamics simulation. Calculation of molecular electrostatic potentials revealed that the binding site of OpB is more negative than that of PEP, in accordance with the experimentally observed selectivity of OpB towards proteolysis at dibasic sites. A recently developed Monte Carlo docking method was used provide a structural rationale for the affinity differences measured between Z-Arg and Z-Arg-Arg substrates.

Amino Acid Sequence↗

PubMed2005

Molecular basis of the interaction specificity between the human glucocorticoid receptor and its endogenous steroid ligand cortisol.

We analyzed the binding of five steroids to the human glucocorticoid receptor (hGR) experimentally as well as theoretically. In vitro, we measured the binding affinity of aldosterone, cortisol, estradiol, progesterone, and testosterone to hGR in competition with the ligand dexamethasone. The binding affinity relative to the endogenous ligand cortisol (100%) is reduced for progesterone (22%) and aldosterone (20%) and is very weak for testosterone (1.5%) and estradiol (0.2%). In parallel, we constructed a homology model of the hGR ligand-binding domain (LBD) based on the crystal structure of the human progesterone receptor (hPR). After docking the five steroids into the hGR model ligand-binding pocket, we performed five separate 4-ns molecular dynamics (MD) simulations with these complexes in order to study the complex structures. We calculated the binding affinities with two different approaches (MM/PBSA, FlexX) and compared them with the values of the experimentally determined relative binding affinities. Both theoretical methods allowed discrimination between strongly and weakly binding ligands and recognition of cortisol as the endogenous ligand of the hGR in silico. Cortisol binds most strongly due to a nearly perfect steric and electrostatic complementarity with the hGR binding pocket. Chemically similar ligands such as estradiol, testosterone, and progesterone also fit into the hGR binding pocket, but they are unable to form all those contacts with the amino acids of the protein that are necessary to yield a stable, transcriptionally active receptor conformation. Our analysis thus explains the selectivity of the human glucocorticoid receptor for its endogenous ligand cortisol at a molecular level.

Amino Acids↗

PubMed2006

Fully flexible docking models of the complex between alpha7 nicotinic receptor and a potent heptapeptide inhibitor of the beta-amyloid peptide binding.

The heptapeptide IQTTWSR (IQ), recently reported as inhibitor of the beta-amyloid (Abeta) binding to nicotinic acetylcholine receptors (nAChrs), was docked to the homology model of the alpha7 nicotinic acetylcholine receptor. The most representative models were further subjected to molecular dynamics simulations. The data obtained here suggest that Abeta needs highly specific structural motifs to bind to the alpha7nAChR. These structural motifs are located principally in the upper and lower surroundings of loop C, including loop F and sheets beta1, beta2, beta6, beta9, and beta10 of the receptor. Overall, these results suggest that IQ can be mimicked by more bioavailable, stable compounds that would be helpful for the understanding of the Abeta binding site and its dynamics, and for the design of novel agents to be used as an effective alternative against Alzheimer's disease.

Amyloid beta-Peptides↗

PubMed2005

"In situ cross-docking" to simultaneously address multiple targets.

In standard docking, every target structure requires separate docking calculations. To overcome this limitation, an approach is presented by which multiple proteins can be addressed simultaneously in a single docking run. This "in situ cross-docking" is built on a grid-based docking method and follows the idea that grids calculated for single binding sites may be joined to one common grid. Docking then allows for a direct selection of the optimal target by the ligand being docked. The approach is technically feasible and can lead to significant time savings over conventional cross-docking.

Algorithms↗

PubMed2002

Models@Home: distributed computing in bioinformatics using a screensaver based approach.

MOTIVATION: Due to the steadily growing computational demands in bioinformatics and related scientific disciplines, one is forced to make optimal use of the available resources. A straightforward solution is to build a network of idle computers and let each of them work on a small piece of a scientific challenge, as done by Seti@Home (http://setiathome.berkeley.edu), the world's largest distributed computing project. RESULTS: We developed a generally applicable distributed computing solution that uses a screensaver system similar to Seti@Home. The software exploits the coarse-grained nature of typical bioinformatics projects. Three major considerations for the design were: (1) often, many different programs are needed, while the time is lacking to parallelize them. Models@Home can run any program in parallel without modifications to the source code; (2) in contrast to the Seti project, bioinformatics applications are normally more sensitive to lost jobs. Models@Home therefore includes stringent control over job scheduling; (3) to allow use in heterogeneous environments, Linux and Windows based workstations can be combined with dedicated PCs to build a homogeneous cluster. We present three practical applications of Models@Home, running the modeling programs WHAT IF and YASARA on 30 PCs: force field parameterization, molecular dynamics docking, and database maintenance.

Computational Biology↗

PubMed2001

A modeling study of the interaction and electron transfer between cytochrome b5 and some oxidized haemoglobins.

Using Brownian motion simulations we have studied the formation of docked complexes of reduced cytochrome b5 and oxidized haemoglobin. Our results indicate that the presence of molecular electrostatic fields has a significant role to play in the formation of these complexes. In contrast to previous modeling studies on this system, we clearly identify electron transfer within an ensemble of similarly docked complexes rather than the formation of a single complex. Docking involves a number of acidic residues surrounding the exposed haem edge of cytochrome b5 and a set of basic residues surrounding the exposed haem edge of the globins. Although amino acids from the partner globin proteins are involved to a small extent in the binding of some of the complexes, the reactivity of any particular globin is essentially independent of the nature of its partner globin chain within the haemoglobin molecule. Comparison of results from adult and embryonic haemoglobins indicates a significant difference in complex formation. Application of electron tunneling analysis to the complexes allows us to predict the rates of electron transfer within each ensemble of complexes. These data provide a theoretical insight into the important process of re-reduction of oxidized haemoglobins as well as explaining the general inability to produce crystalline forms of many docked electron transfer complexes.

Computer Simulation↗

PubMed2004

On the modeling of snake venom serine proteinase interactions with benzamidine-based thrombin inhibitors.

Pit viper venoms contain a number of serine proteinases that exhibit one or more thrombin-like activities on fibrinogen and platelets, this being the case for the kinin-releasing and fibrinogen-clotting KN-BJ from the venom of Bothrops jararaca. A three-dimensional structural model of the KN-BJ2 serine proteinase was built by homology modeling using the snake venom plasminogen activator TSV-PA as a major template and porcine kallikrein as additional structural support. A set of intrinsic buried waters was included in the model and its behavior under dynamic conditions was molecular dynamics simulated, revealing a most interesting similarity pattern to kallikrein. The benzamidine-based thrombin inhibitors alpha-NAPAP, 3-TAPAP, and 4-TAPAP were docked into the refined model, allowing for a more insightful functional characterization of the enzyme and a better understanding of the reported comparatively low affinity of KN-BJ2 toward those inhibitors.

Amidines↗

PubMed1997

Altered acyl chain length specificity of Rhizopus delemar lipase through mutagenesis and molecular modeling.

The acyl binding site of Rhizopus delemar prolipase and mature lipase was altered through site-directed mutagenesis to improve lipase specificity for short- or medium-chain length fatty acids. Computer-generated structural models of R. delemar lipase were used in mutant protein design and in the interpretation of the catalytic properties of the resulting recombinant enzymes. Molecular dynamics simulations of the double mutant, val209trp + phe112trp, predicted that the introduction of trp112 and trp209 in the acyl binding groove would sterically hinder the docking of fatty acids longer than butyric acid. Assayed against a mixture of triacylglycerol substrates, the val209trp + phe112trp mature lipase mutant showed an 80-fold increase in the hydrolysis of tributyrin relative to the hydrolysis of tricaprylin while no triolein hydrolysis was detected. By comparison, the val94Trp mutant, predicted to pose steric or geometric constraints for docking fatty acids longer than caprylic acid in the acyl binding groove, resulted in a modest 1.4-fold increase in tricaprylin hydrolysis relative to the hydrolysis of tributyrin. Molecular models of the double mutant phe95asp + phe214arg indicated the creation of a salt bridge between asp95 and arg214 across the distal end of the acyl binding groove. When challenged with a mixture of triacylglycerols, the phe95asp + phe214arg substitutions resulted in an enzyme with 3-fold enhanced relative activity for tricaprylin compared to triolein, suggesting that structural determinants for medium-chain length specificity may reside in the distal end of the acyl binding groove. Attempts to introduce a salt bridge within 8 A of the active site by the double mutation leu146lys + ser115asp destroyed catalytic activity entirely. Similarly, the substitution of polar Gln at the rim of the acyl binding groove for phe112 largely eliminated catalytic activity of the lipase.

Caprylates↗

PubMed2000

A method for including protein flexibility in protein-ligand docking: improving tools for database mining and virtual screening.

Second-generation methods for docking ligands into their biological receptors, such as FLOG, provide for flexibility of the ligand but not of the receptor. Molecular dynamics based methods, such as free energy perturbation, account for flexibility, solvent effects, etc., but are very time consuming. We combined the use of statistical analysis of conformational samples from short-run protein molecular dynamics with grid-based docking protocols and demonstrated improved performance in two test cases. Our statistical analysis explores the importance of the average strength of a potential interaction with the biological target and optionally applies a weighting depending on the variability in the strength of the interaction seen during dynamics simulation. Using these methods, we improved the num-top-ranked 10% of a database of drug-like molecules, in searches based on the three-dimensional structure of the protein. These methods are able to match the ability of manual docking to assess likely inactivity on steric grounds and indeed to rank order ligands from a homologous series of cyclooxygenase-2 inhibitors with good correlation to their true activity. Furthermore, these methods reduce the need for human intervention in setting up molecular docking experiments.

Combinatorial Chemistry Techniques↗

PubMed2005

The protein-protein interactions between SMPI and thermolysin studied by molecular dynamics and MM/PBSA calculations.

Thermolysin is a zinc-metalloendopeptidase secreted by the gram-positive thermophilic bacterium Bacillus thermoproteolyticus. Thermolysin belongs to the gluzinicin family of enzymes, which is selectively inhibited by Steptomyces metalloproteinase inhibitor (SMPI). Very little is known about the interaction between SMPI and thermolysin. Knowledge about the protein-protein interactions is very important for designing new thermolysin inhibitors with possible industrial or pharmaceutical applications. In the present study, two binding modes between SMPI and thermolysin were studied by 2300 picoseconds (ps) of comparative molecular dynamics (MD) simulations and calculation of the free energy of binding using the molecular mechanics-Poisson-Boltmann surface area (MM/PBSA) method. One of the positions, the 'horizontal arrow head docking' (HAHD) was similar to the previously proposed binding mode by Tate et al. (Tate, S., Ohno, A., Seeram, S. S., Hiraga, K., Oda, K., and Kainosho, M. J. Mol. Biol. 282, 435-446 (1998)). The other position, the 'vertical arrow head docking' (VAHD) was obtained by a manual docking guided by the shape and charge distribution of SMPI and the binding pocket of thermolysin. The calculations showed that SMPI had stronger interactions with thermolysin in the VAHD than in the HAHD complex, and the VAHD complex was considered more realistic than the HAHD complex. SMPI interacted with thermolysin not only at the active site but had auxiliary binding sites contributing to proper interactions. The VAHD complex can be used for designing small molecule inhibitors mimicking the SMPI-thermolysin binding interfaces.

Bacillus↗

PubMed1992

Molecular dynamics study of a complex between the human histocompatibility antigen HLA-A2 and the IMP58-66 nonapeptide from influenza virus matrix protein.

The structure of the influenza-virus-matrix-protein (IMP) 58-66 nonapeptide, bound to the major-histocompatibility-complex-encoded human leukocyte antigen (HLA) A2 protein was studied by molecular dynamics simulation. Starting from the extra electron density map of peptides co-crystallized with HLA-A2, the nonapeptide IMP58-66 was docked residue by residue in the protein binding cleft. The complex was simulated for 100 ps in a shell of 1372 water molecules. The averaged simulated HLA-A2 conformation was found to be similar to the crystal structure (0.182 nm RMS deviation, for the backbone atoms of the alpha 1-alpha 2 domain). Nine out of the 14 hydrogen bonds observed in the antigen-binding site were reproduced in the simulation. The IMP58-66 peptide exhibits an extended conformation with kinks at positions 3 and 5. The side chains of residues 2, 3 and 9 develop van der Waals' interactions with hydrophobic pockets of HLA-A2, corresponding to polymorphic residues of the major-histocompatibility-complex-encoded proteins. Both the N-terminus and C-terminus of the nonapeptide were anchored in the antigen-binding groove by hydrogen bonds with conserved amino acids. The N-terminus was more flexible and contacts four HLA-A2 conserved tyrosines (Tyr7, Tyr59, Tyr159 and Tyr171) and Glu63 by direct or water-relayed hydrogen bonds. Water intercalation occurred only around the N-terminus of the peptide, the C-terminal carboxylate forming strong hydrogen bonds with polar residues (Tyr84 and Thr143) and a salt bridge with Lys146 all over the molecular dynamics simulation. This model is fully compatible with the recently published crystal structure of the HLA-B27 protein, complexed by a mixture of self nonapeptides.

Amino Acid Sequence↗

PubMedDate not supplied

Are automated molecular dynamics simulations and binding free energy calculations realistic tools in lead optimization? An evaluation of the linear interaction energy (LIE) method.

An extensive evaluation of the linear interaction energy (LIE) method for the prediction of binding affinity of docked compounds has been performed, with an emphasis on its applicability in lead optimization. An automated setup is presented, which allows for the use of the method in an industrial setting. Calculations are performed for four realistic examples, retinoic acid receptor gamma, matrix metalloprotease 3, estrogen receptor alpha, and dihydrofolate reductase, focusing on different aspects of the procedure. The obtained LIE models are evaluated in terms of the root-mean-square (RMS) errors from experimental binding free energies and the ability to rank compounds appropriately. The results are compared to the best empirical scoring function, selected from a set of 10 scoring functions. In all cases, good LIE models can be obtained in terms of free-energy RMS errors, although reasonable ranking of the ligands of dihydrofolate reductase proves difficult for both the LIE method and scoring functions. For the other proteins, the LIE model results in better predictions than the best performing scoring function. These results indicate that the LIE approach, as a tool to evaluate docking results, can be a valuable asset in computational lead optimization programs.

Automation↗

PubMed2006

A multistep approach to structure-based drug design: studying ligand binding at the human neutrophil elastase.

In this study we show that a combination of different theoretical methods is a viable approach to calculate the binding affinities of new ligands for the human neutrophile elastase. This protease degrades elastin and likely aids neutrophils in fulfilling their immunological functions. Abnormally high human neutrophil elastase (HNE) levels are involved in several diseases; therefore, inhibitors of HNE are of interest as targets for drug design. A recent study has revealed that cinnamic acid and bornyl ester derivatives bind to HNE, but DeltaG0 values from ligand docking results exhibited no correlation with those calculated from the IC50 values. To accurately compute binding affinities, we generated possible protein ligand complex structures by ligand docking calculations. For each of the ligands, the 30 most likely placements were used as starting points of nanosecond length molecular dynamics simulations. The binding free energies for these complex structures were estimated using a continuum solvent (MM-PBSA) approach. These results, along with structural data from the molecular dynamics runs, allowed the identification of a group of similar placements that serve as a model for the natural protein ligand complex structure. This structural model was used to perform thermodynamic integration (TI) calculations to obtain the relative binding free energies of similar ligands to HNE. The TI results were in quantitative agreement with the measured binding affinities. Thus, the presented approach can be used to generate a probable complex structure for known ligands to HNE and to use such a structure to calculate the effects of small ligand modifications on ligand binding, possibly leading to new inhibitors with improved binding affinities.

Binding Sites↗

PubMed1999

Integrating computation and visualization for biomolecular analysis: an example using python and AVS.

One of the challenges in biocomputing is to enable the efficient use of a wide variety of fast-evolving computational methods to simulate, analyze, and understand the complex properties and interactions of molecular systems. Our laboratory investigates several areas including molecular visualization, protein-ligand docking, protein-protein docking, molecular surfaces, and the derivation of phenomenological potentials. In this paper we present an approach based on the Python programming language to achieve a high level of integration between these different computational methods and our primary visualization system AVS. This approach removes many limitations of AVS while increasing dramatically the inter-operability of our computational tools. Several examples are shown to illustrate how this approach enables a high level of integration and inter-operability between different tools, while retaining modularity and avoiding the creation of a large monolithic package that is difficult to extend and maintain.

Capsid↗

PubMed2005

Comparative molecular dynamics simulations of HIV-1 integrase and the T66I/M154I mutant: binding modes and drug resistance to a diketo acid inhibitor.

HIV-1 IN is an essential enzyme for viral replication and an interesting target for the design of new pharmaceuticals for use in multidrug therapy of AIDS. L-731,988 is one of the most active molecules of the class of beta-diketo acids. Individual and combined mutations of HIV-1 IN at residues T66, S153, and M154 confer important degrees of resistance to one or more inhibitors belonging to this class. In an effort to understand the molecular mechanism of the resistance of T66I/M154I IN to the inhibitor L-731,988 and its specific binding modes, we have carried out docking studies, explicit solvent MD simulations, and binding free energy calculations. The inhibitor was docked against different protein conformations chosen from prior MD trajectories, resulting in 2 major orientations within the active site. MD simulations have been carried out for the T66I/M154I DM IN, DM IN in complex with L-731,988 in 2 different orientations, and 1QS4 IN in complex with L-731,988. The results of these simulations show a similar dynamical behavior between T66I/M154I IN alone and in complex with L-731,988, while significant differences are observed in the mobility of the IN catalytic loop (residues 138-149). Water molecules bridging the inhibitor to residues from the active site have been identified, and residue Gln62 has been found to play an important role in the interactions between the inhibitor and the protein. This work provides information about the binding modes of L-731,988, as well as insight into the mechanism of inhibitor-resistance in HIV-1 integrase.

Amino Acid Substitution↗