ArticleProtein science : a publication of the Protein Society2010
A flexible docking scheme to explore the binding selectivity of PDZ domains.
Article in Protein science : a publication of the Protein Society, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 22 papers.
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22 citing papers in PubMed.
- Topological metrics as evolutionary and dynamical descriptors of conformational landscapes within protein families.PLoS computational biology · 2026Article
- Viral subversion of the cell polarity regulator Scribble.Biochemical Society transactions · 2023Review
- Substitutions at Nonconserved Rheostat Positions Modulate Function by Rewiring Long-Range, Dynamic Interactions.Molecular biology and evolution · 2021Article
- Specificity in PDZ-peptide interaction networks: Computational analysis and review.Journal of structural biology: X · 2020Review
- Ancient thioredoxins evolved to modern-day stability-function requirement by altering native state ensemble.Philosophical transactions of the Royal Society of London. Series B, Biological sciences · 2018Article
- Structure function relations in PDZ-domain-containing proteins: Implications for protein networks in cellular signalling.Journal of biosciences · 2018Review
- Flexibility-rigidity index for protein-nucleic acid flexibility and fluctuation analysis.Journal of computational chemistry · 2016Article
- Multiscale Gaussian network model (mGNM) and multiscale anisotropic network model (mANM).The Journal of chemical physics · 2015Article
- Fast and anisotropic flexibility-rigidity index for protein flexibility and fluctuation analysis.The Journal of chemical physics · 2014Article
- Elastic network models capture the motions apparent within ensembles of RNA structures.RNA (New York, N.Y.) · 2014Article
- BP-Dock: a flexible docking scheme for exploring protein-ligand interactions based on unbound structures.Journal of chemical information and modeling · 2014Article
- A flexible docking scheme efficiently captures the energetics of glycan-cyanovirin binding.Biophysical journal · 2014Article
- New conformational state of NHERF1-CXCR2 signaling complex captured by crystal lattice trapping.PloS one · 2013Article
- The role of flexibility and conformational selection in the binding promiscuity of PDZ domains.PLoS computational biology · 2012Article
- From laptop to benchtop to bedside: structure-based drug design on protein targets.Current pharmaceutical design · 2012Review
- Change in allosteric network affects binding affinities of PDZ domains: analysis through perturbation response scanning.PLoS computational biology · 2011Review
- Multiple-targeting and conformational selection in the estrogen receptor: computation and experiment.Chemical biology & drug design · 2011Article
- Predictive power of molecular dynamics receptor structures in virtual screening.Journal of chemical information and modeling · 2011Article
- Putting into practice domain-linear motif interaction predictions for exploration of protein networks.PloS one · 2011Article
- Crystallographic and nuclear magnetic resonance evaluation of the impact of peptide binding to the second PDZ domain of protein tyrosine phosphatase 1E.Biochemistry · 2010Article
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2 authors.
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Abstract
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 A. 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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