Flexible ligand docking to multiple receptor conformations: a practical alternative

Totrov, Maxim; Abagyan, Ruben

doi:10.1016/j.sbi.2008.01.004

Cited by 447 publications

(395 citation statements)

References 33 publications

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“…Docking algorithms predict the incorrect binding pose for about 50-70% of all ligands when the receptor is kept in single position. 7 Overall, induced flexibility is the key ingredient to understand the physical principles of molecular recognition between ligand and receptor. It has been shown that even small changes in receptor upon binding can be important in computing the binding affinities.…”

Section: Introductionmentioning

confidence: 99%

A flexible docking scheme to explore the binding selectivity of PDZ domains

Gerek

Ozkan

2010

Protein Science

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Modeling of protein binding site flexibility in molecular docking is still a challenging problem due to the large conformational space that needs sampling. Here, we propose a flexible receptor docking scheme: A dihedral restrained replica exchange molecular dynamics (REMD), where we incorporate the normal modes obtained by the Elastic Network Model (ENM) as dihedral restraints to speed up the search towards correct binding site conformations. To our knowledge, this is the first approach that uses ENM modes to bias REMD simulations towards binding induced fluctuations in docking studies. In our docking scheme, we first obtain the deformed structures of the unbound protein as initial conformations by moving along the binding fluctuation mode, and perform REMD using the ENM modes as dihedral restraints. Then, we generate an ensemble of multiple receptor conformations (MRCs) by clustering the lowest replica trajectory. Using ROSETTALIGAND, we dock ligands to the clustered conformations to predict the binding pose and affinity. We apply this method to postsynaptic density-95/Dlg/ZO-1 (PDZ) domains; whose dynamics govern their binding specificity. Our approach produces the lowest energy bound complexes with an average ligand root mean square deviation of 0.36 Å . We further test our method on (i) homologs and (ii) mutant structures of PDZ where mutations alter the binding selectivity. In both cases, our approach succeeds to predict the correct pose and the affinity of binding peptides. Overall, with this approach, we generate an ensemble of MRCs that leads to predict the binding poses and specificities of a protein complex accurately.

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Section: Introductionmentioning

confidence: 99%

A flexible docking scheme to explore the binding selectivity of PDZ domains

Gerek

Ozkan

2010

Protein Science

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“…In total, this results in docking to an ensemble of different (fixed) receptor conformations, thereby implicitly taking into account conformational changes upon binding. 31 Molecular dynamics (MD) simulation 32 is the state-ofthe-art tool to generate conformational ensembles of biomacromolecules at an atomic level. Enhanced sampling methods, such as replica exchange molecular dynamics (REMD), 33 are increasingly used to overcome barriers between local minima.…”

Section: Introductionmentioning

confidence: 99%

HIV-1 TAR RNA Spontaneously Undergoes Relevant Apo-to-Holo Conformational Transitions in Molecular Dynamics and Constrained Geometrical Simulations

Fulle

Christ

Kestner

et al. 2010

J. Chem. Inf. Model.

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We report all-atom molecular dynamics and replica exchange molecular dynamics simulations on the unbound human immunodeficiency virus type-1 (HIV-1) transactivation responsive region (TAR) RNA structure and three TAR RNA structures in bound conformations of, in total, ∼250 ns length. We compare the extent of observed conformational sampling with that of the conceptually simpler and computationally much cheaper constrained geometrical simulation approach framework rigidity optimized dynamic algorithm (FRODA). Atomic fluctuations obtained by replica-exchange molecular dynamics (REMD) simulations agree quantitatively with those obtained by molecular dynamics (MD) and FRODA simulations for the unbound TAR structure. Regarding the stereochemical quality of the generated conformations, backbone torsion angles and puckering modes of the sugar-phosphate backbone were reproduced equally well by MD and REMD simulations, but further improvement is needed in the case of FRODA simulations. Essential dynamics analysis reveals that all three simulation approaches show a tendency to sample bound conformations when starting from the unbound TAR structure, with MD and REMD simulations being superior with respect to FRODA. These results are consistent with the experimental view that bound TAR RNA conformations are transiently sampled in the free ensemble, following a conformation selection model. The simulation-generated TAR RNA conformations have been successfully used as receptor structures for docking. This finding has important implications for RNA-ligand docking in that docking into an ensemble of simulation-generated RNA structures is shown to be a valuable means to cope with large apo-to-holo conformational transitions of the receptor structure.

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“…Identifying inhibitors by virtual screening involves multiple steps, and its success depends on several factors: the efficiency of ligand and receptor conformational sampling (4)(5)(6)(7)(8)(9)(10)(11), the quality of the scoring function (12,13), the choice of docking pocket, and finally, the availability of a relevant assay to test the virtual screening candidates.…”

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confidence: 99%

Use of allostery to identify inhibitors of calmodulin-induced activation of Bacillus anthracis edema factor

Laine

Gonçalves

Karst

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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Allostery plays a key role in the regulation of the activity and function of many biomolecules. And although many ligands act through allostery, no systematic use is made of it in drug design strategies. Here we describe a procedure for identifying the regions of a protein that can be used to control its activity through allostery. This procedure is based on the construction of a plausible conformational path, which describes protein transition between known active and inactive conformations. The path is calculated by using a framework approach that steers and markedly improves the conjugate peak refinement method. The evolution of conformations along this path was used to identify a putative allosteric site that could regulate activation of Bacillus anthracis adenylyl cyclase toxin (EF) by calmodulin. Conformations of the allosteric site at different steps along the path from the inactive (free) to the active (bound to calmodulin) forms of EF were used to perform virtual screenings and propose candidate EF inhibitors. Several candidates then proved to inhibit calmodulin-induced activation in an in vitro assay. The most potent compound fully inhibited EF at a concentration of 10 μM. The compounds also inhibited the related adenylyl cyclase toxin from Bordetella pertussis (CyaA). The specific homology between the putative allosteric sites in both toxins supports that these pockets are the actual binding sites of the selected inhibitors.anthrax | transition path calculation | molecular dynamics | drug discovery | inhibition of protein-protein association

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Flexible ligand docking to multiple receptor conformations: a practical alternative

Cited by 447 publications

References 33 publications

A flexible docking scheme to explore the binding selectivity of PDZ domains

A flexible docking scheme to explore the binding selectivity of PDZ domains

HIV-1 TAR RNA Spontaneously Undergoes Relevant Apo-to-Holo Conformational Transitions in Molecular Dynamics and Constrained Geometrical Simulations

Use of allostery to identify inhibitors of calmodulin-induced activation of Bacillus anthracis edema factor

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