An Efficient Metadynamics-Based Protocol To Model the Binding Affinity and the Transition State Ensemble of G-Protein-Coupled Receptor Ligands
Saleh N, Ibrahim P, Saladino G, Gervasio FL, Clark T (2017)
Publication Status: Published
Publication Type: Journal article
Publication year: 2017
Journal
Publisher: AMER CHEMICAL SOC
Book Volume: 57
Pages Range: 1210-1217
Journal Issue: 5
Abstract
A generally applicable metadynamics scheme for predicting the free energy profile of ligand binding to G-protein-coupled receptors (GPCRs) is described. A common and effective collective variable (CV) has been defined using the ideally placed and highly conserved Trp6.48 as a reference point for ligand GPCR distance measurement and the common orientation of GPCRs in the cell membrane. Using this single CV together with well-tempered multiple-walker metadynamics with a funnel-like boundary allows an efficient exploration of the entire ligand binding path from the extracellular medium to the orthosteric binding site, including vestibule and intermediate sites. The protocol can be used with X-ray structures or high-quality homology models (based on a high-quality template and after thorough refinement) for the receptor and is universally applicable to agonists, antagonists, and partial and reverse agonists. The root-mean-square error (RMSE) in predicted binding free energies for 12 diverse ligands in five receptors (a total of 23 data points) is surprisingly small (less than 1 kcal mol(-1)). The RMSEs for simulations that use receptor X-ray structures and homology models are very similar.
Authors with CRIS profile
Noureldin Saleh
Computer-Chemie-Centrum
Passainte Ibrahim
Computer-Chemie-Centrum
Timothy Clark
Computer-Chemie-Centrum
Involved external institutions
United Kingdom (GB)How to cite
APA:
Saleh, N., Ibrahim, P., Saladino, G., Gervasio, F.L., & Clark, T. (2017). An Efficient Metadynamics-Based Protocol To Model the Binding Affinity and the Transition State Ensemble of G-Protein-Coupled Receptor Ligands. Journal of Chemical Information and Modeling, 57(5), 1210-1217. https://dx.doi.org/10.1021/acs.jcim.6b00772
MLA:
Saleh, Noureldin, et al. "An Efficient Metadynamics-Based Protocol To Model the Binding Affinity and the Transition State Ensemble of G-Protein-Coupled Receptor Ligands." Journal of Chemical Information and Modeling 57.5 (2017): 1210-1217.
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