Rxivist combines preprints from bioRxiv with data from Twitter to help you find the papers being discussed in your field. Currently indexing 57,793 bioRxiv papers from 266,023 authors.
Agonist binding to the extracellular part of G protein-coupled receptors (GPCRs) leads to conformational changes in the transmembrane region that activate cytosolic signalling pathways. Although high resolution structures of the inactive and active receptor states are available, the allosteric coupling that transmits the signal across the membrane is not fully understood. We calculated free energy landscapes of the β2 adrenergic receptor using atomistic molecular dynamics simulations in an optimized string-of-swarms framework, which sheds new light on the roles of microswitches involved in activation. Contraction of the extracellular binding site in the presence of agonist is obligatorily coupled to conformational changes in a connector motif located in the core of the transmembrane region. In turn, the connector is probabilistically coupled to the conformation of the intracellular region. An active connector promotes desolvation of a buried solvent-filled cavity and a twist of the conserved NPxxY motif, which leads to a larger population of active-like states at the G protein binding site. This effect is further augmented by protonation of the strongly conserved Asp79, which locks the NPxxY motif and solvent cavity in active-like conformations. The agonist binding site hence communicates with the intracellular region via a cascade of locally connected switches and the free energy landscapes along these contributes to understanding of how ligands can stabilize distinct receptor states. We demonstrate that the developed simulation protocol is transferable to other class A GPCRs and anticipate that it will become a useful tool in design of drugs with specific signaling properties.
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