Universiteit Leiden

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Research project

Binding mode characterization using free energy perturbations

Supervisors: Bart Lenselink (Leiden University) / Willem Jespers (Uppsala University)

Gerard van Westen

The growing availability of G Protein-Coupled Receptor (GPCR) crystal structures increases the structural and functional knowledge on this important class of membrane proteins. The combination of experimental methods, like site directed mutagenesis methods such as biophysical mapping (BPM),1 and computational methods like free energy perturbations (FEP)2 allow for a more detailed analysis of the structural influence of residues on ligand binding.

This combination of methods has recently been benchmarked on crystal structure ligands for the adenosine A2A receptor,3,4 and has been further extended to non crystalized ligands (unpublished data). In combination with the recent effort of the GPCRdb 5 to collect mutagenesis data for all GPCRs, there is a potential to reliably predict binding modes for ligands that have not yet been co-crystalized.

The project will consist of two parts. The first will entail the characterization of a set of reference ligands for the adenosine receptor family, for which all available mutagenesis data has recently been collected (unpublished data). The second will be to test the applicability of the obtained reference ligand complexes in virtual screening.

(1) Langmead, C. J.; Andrews, S. P.; Congreve, M.; Errey, J. C.; Hurrell, E.; Marshall, F. H.; Mason, J. S.; Richardson, C. M.; Robertson, N.; Zhukov, A.; Weir, M. Identification of Novel Adenosine A(2A) Receptor Antagonists by Virtual Screening. J. Med. Chem. 2012, 55 (5), 1904–1909.

(2) Boukharta, L.; Gutiérrez-de-Terán, H.; Åqvist, J. Computational Prediction of Alanine Scanning and Ligand Binding Energetics in G-Protein Coupled Receptors. PLoS Comput. Biol. 2014, 10 (4), e1003585.

(3) Keränen, H.; Gutiérrez-de-Terán, H.; Åqvist, J. Structural and Energetic Effects of A2A Adenosine Receptor Mutations on Agonist and Antagonist Binding. PLoS One 2014, 9 (10), e108492.

(4) Keränen, H.; Åqvist, J.; Gutiérrez-de-Terán, H. Free Energy Calculations of A 2A Adenosine Receptor Mutation Effects on Agonist Binding. Chem. Commun. 2015, 51 (17), 3522–3525.

(5) Isberg, V.; Vroling, B.; van der Kant, R.; Li, K.; Vriend, G.; Gloriam, D. GPCRDB: An Information System for G Protein-Coupled Receptors. Nucleic Acids Res. 2014, 42 (Database issue), D422–D425.

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