G-protein-coupled receptors (GPCRs) mediate various cellular responses in the human body. More than one third of the clinical drugs target on GPCRs to regulate their activation and coupling to G-proteins. Investigation of signal transmission from GPCRs to the G-proteins is thus of great importance for designing better GPCR modulators. The breakthrough in the crystallography of GPCR-G protein complexes has greatly facilitated our study of GPCRs. However, how G-proteins couple to GPCRs to complete the regulation of the human body is still unclear. Here, we carried out steered molecular dynamics simulations (SMDs) to study the release of a G-protein from a prototype of GPCR, the �2-adrenergic receptor. Umbrella sampling of selected states along the releasing pathway was explored to produce the potential of mean force for the uncoupling of the G-protein from the GPCR and detailed information of the G-protein release is elucidated. Our results can be helpful in understanding the signal transmission from GPCRs to the downstream proteins and may provide us with a new perspective on designing molecules regulating G-protein binding.

Computational investigation of G-proteins releasing from G-protein-coupled receptors

246th National Meeting (2013)

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