An Efficient Metadynamics-Based Protocol To Model the Binding Affinity and the Transition State Ensemble of G-Protein-Coupled Receptor Ligands

Beitrag in einer Fachzeitschrift


Details zur Publikation

Autor(en): Saleh N, Ibrahim P, Saladino G, Gervasio FL, Clark T
Zeitschrift: Journal of Chemical Information and Modeling
Verlag: AMER CHEMICAL SOC
Jahr der Veröffentlichung: 2017
Band: 57
Heftnummer: 5
Seitenbereich: 1210-1217
ISSN: 1549-9596


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.


FAU-Autoren / FAU-Herausgeber

Clark, Timothy apl. Prof. Dr.
Computer-Chemie-Centrum
Ibrahim, Passainte
Computer-Chemie-Centrum
Saleh, Noureldin
Computer-Chemie-Centrum


Autor(en) der externen Einrichtung(en)
University College London (UCL) (University of London)


Zitierweisen

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.

BibTeX: 

Zuletzt aktualisiert 2019-13-01 um 07:09