Nicoleta Bondar
Affiliation
University of Bucharest, Romania
Dynamic hydrogen-bond networks for G Protein Coupled Receptor activation
Co-authors
Eva Bertalan,1 Matthew J. Rodrigues,2 Ching-Ju Tsai,3 Gebhard F.X. Schertler,3 and Ana-Nicoleta Bondar4,5
1Physikzentrum, RWTH-Aachen University, Aachen, Germany; 2Diamond Light Source, Harwell Science and Innovation Campus, Didcot OX11 0DE, United Kingdom; 3Paul Scherrer Institut, Laboratory of Biomolecular Research, ETH Zürich, CH-5232 Villigen, Switzerland; 4University of Bucharest, Faculty of Physics, Atomiștilor 405, Măgurele 077125, Romania; 5Forschungszentrum Jülich, Institute for Neuroscience and Medicine (INM), Computational Biomedicine (INM-9), Wilhelm-Johnen Straße, 5428 Jülich, Germany.
Abstract
G Protein Coupled Receptors use hydrogen(H)-bond networks to couple ligand binding with protein conformational dynamics, activation, and the binding of cytoplasmic interaction partners. These long-distance H-bond networks are typically mediated by water molecules, tend to be dynamic, and can include titratable residues whose protonation changes during receptor function. To study the role of dynamic protein-water hydrogen-bond networks in GPCRs we developed graph-based algorithms and tools. DNET, our most recent computational workflow and graph-based tool, enables efficient computations of protein-water H-bond networks, estimates of pKa values for titratable residues of the H-bond network, and potential of mean force for pairwise distances between residues that are nodes of the graph. We apply DNET to study the assembly and role of internal H-bond networks in a visual receptor of interest as optogenetic tool. From multiple simulations of wild-type and mutant receptors we find that about half of the H-bond network at the ligand-binding site consists of interactions with one conformational mode; the other half of the network consists of interactions that are more dynamic, with two or more conformational modes. H-bonds with more than one conformational mode could help facilitate the propagation of changes in receptor structure and dynamics during activation.