Journal
JOURNAL OF CHEMICAL INFORMATION AND MODELING
Volume 57, Issue 5, Pages 1210-1217Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.jcim.6b00772
Keywords
-
Categories
Funding
- Deutsche Forschungsgemeinschaft [GRK1910]
- Leibniz Rechenzentrum, Munich [pr94to, pr74su]
- EPSRC [EP/M013898/1]
- EPSRC [EP/M013898/1, EP/P011306/1, EP/L000253/1, EP/M022609/1] Funding Source: UKRI
- Engineering and Physical Sciences Research Council [EP/P011306/1, EP/M022609/1, EP/L000253/1, EP/M013898/1] Funding Source: researchfish
Ask authors/readers for more resources
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
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available