{"id":3272,"date":"2025-11-22T09:43:34","date_gmt":"2025-11-22T14:43:34","guid":{"rendered":"https:\/\/www.med.unc.edu\/pharm\/miaolab\/?p=3272"},"modified":"2025-12-05T09:54:49","modified_gmt":"2025-12-05T14:54:49","slug":"new-paper-on-dissociation-kinetics-of-g-proteins","status":"publish","type":"post","link":"https:\/\/www.med.unc.edu\/pharm\/miaolab\/2025\/11\/new-paper-on-dissociation-kinetics-of-g-proteins\/","title":{"rendered":"New paper on &#8220;Dissociation kinetics of G proteins from G protein\u2013coupled receptors and effects of allosteric modulation&#8221;"},"content":{"rendered":"<p>Congratulations to Jinan and Victor for a new paper published in <em>PNAS<\/em> on &#8220;<strong><a href=\"https:\/\/www.pnas.org\/doi\/10.1073\/pnas.2512423122\" target=\"_blank\" rel=\"noopener\">Dissociation kinetics of G proteins from G protein\u2013coupled receptors and effects of allosteric modulation<\/a><\/strong>&#8220;! Really excited to share this story: The PPI-GaMD method developed earlier by Jinan allowed us to capture the &#8220;very slow&#8221; G protein dissociation from GPCRs, a critical event in cellular signaling. The simulations enabled predictions of the G protein dissociation kinetics, which agreed well with experimental data. Together with our experimental collaborators, we also showed that positive allosteric modulators, a new class of selective GPCR drug leads, slowed down the G protein dissociation.<\/p>\n<p>Thanks to Drs. Lauren May, Arthur Christopoulos and Anh Nguyen at Monash University and other team members for the wonderful collaboration!<\/p>\n<h2 id=\"Abs1\" class=\"c-article-section__title js-section-title js-c-reading-companion-sections-item\"><img loading=\"lazy\" decoding=\"async\" class=\"aligncenter wp-image-3274 size-large\" style=\"font-size: 14px\" src=\"https:\/\/www.med.unc.edu\/pharm\/miaolab\/wp-content\/uploads\/sites\/1385\/2025\/11\/PNAS-cover-G-protein-dissociation-white-web-791x1024.jpg\" alt=\"\" width=\"791\" height=\"1024\" srcset=\"https:\/\/www.med.unc.edu\/pharm\/miaolab\/wp-content\/uploads\/sites\/1385\/2025\/11\/PNAS-cover-G-protein-dissociation-white-web-791x1024.jpg 791w, https:\/\/www.med.unc.edu\/pharm\/miaolab\/wp-content\/uploads\/sites\/1385\/2025\/11\/PNAS-cover-G-protein-dissociation-white-web-232x300.jpg 232w, https:\/\/www.med.unc.edu\/pharm\/miaolab\/wp-content\/uploads\/sites\/1385\/2025\/11\/PNAS-cover-G-protein-dissociation-white-web-768x994.jpg 768w, https:\/\/www.med.unc.edu\/pharm\/miaolab\/wp-content\/uploads\/sites\/1385\/2025\/11\/PNAS-cover-G-protein-dissociation-white-web-1187x1536.jpg 1187w, https:\/\/www.med.unc.edu\/pharm\/miaolab\/wp-content\/uploads\/sites\/1385\/2025\/11\/PNAS-cover-G-protein-dissociation-white-web-600x776.jpg 600w, https:\/\/www.med.unc.edu\/pharm\/miaolab\/wp-content\/uploads\/sites\/1385\/2025\/11\/PNAS-cover-G-protein-dissociation-white-web.jpg 1500w\" sizes=\"auto, (max-width: 791px) 100vw, 791px\" \/><\/h2>\n<div id=\"Abs1-content\" class=\"c-article-section__content\">\n<section id=\"executive-summary-abstract\" role=\"doc-abstract\">\n<div style=\"text-align: center\" role=\"paragraph\">Dissociation of G protein from drug-bound GPCR (orange) is captured in accelerated molecular dynamics simulations, starting from the bound (blue) to free state (red), with a trace of its C-terminal residue colored in a blue-white-red scale.<\/div>\n<\/section>\n<section id=\"abstract\" role=\"doc-abstract\">\n<h3>Significance<\/h3>\n<div role=\"paragraph\">Protein\u2013protein interactions (PPIs) are critical in cellular signaling but pose significant challenges for simulations due to slow dynamics. Dissociation of intracellular proteins from G protein\u2013coupled receptors (GPCRs), primary targets of ~1\/3 of marketed drugs, remains unexplored in molecular dynamics (MD) simulations. We have employed a novel PPI-Gaussian accelerated MD (PPI-GaMD) method to investigate dissociation kinetics of G proteins from GPCRs. Our simulations successfully captured G protein dissociation, and the predictions agreed with available experimental data. Further PPI-GaMD simulations and kinetic assays showed that positive allosteric modulators reduced the dissociation rate of G protein from a model GPCR. We have provided insight into GPCR\u2013G protein dissociation kinetics and effects of allosteric modulation. This will facilitate allosteric drug discovery of GPCRs.<\/div>\n<h3>Abstract<\/h3>\n<div role=\"paragraph\">G protein\u2013coupled receptors (GPCRs), the largest superfamily of human membrane proteins with &gt;800 members, are primary targets for ~1\/3 of all marketed drugs. Recent fluorescence experiments underscored the pivotal role of GPCR\u2013G protein complex lifetime in their coupling efficiency and selectivity. However, these experiments are often expensive, time-consuming, and limited to a small number of GPCR\u2013G protein systems. On the other hand, it is challenging to simulate GPCR\u2013G protein dissociation using molecular dynamics (MD) methods. Here, we have employed Protein\u2013Protein Interaction Gaussian accelerated MD (PPI-GaMD) simulations and experiments to probe the kinetics and pathways of G protein dissociation from GPCRs. For five systems with published experimental kinetic data, PPI-GaMD simulations successfully captured G protein dissociation from the GPCRs, including the adrenergic, adenosine, and muscarinic receptors. The simulations allowed identification of two distinct dissociation pathways and calculation of the G protein dissociation rates, which were in good agreement with experimental data. Additionally, we simulated the effect of positive allosteric modulators (PAMs) of the adenosine A<sub>1<\/sub>\u00a0receptor (A<sub>1<\/sub>R) in Gi protein dissociation and supported simulation findings with bioluminescence resonance energy transfer biosensor experiments evaluating G<sub>\u03b2\u03b3<\/sub>\u00a0kinetics following A<sub>1<\/sub>R activation. A<sub>1<\/sub>R PAMs were found to strengthen the agonist\u2013receptor and receptor\u2013G protein interactions and significantly reduce dissociation rates of the Gi protein. In summary, complementary PPI-GaMD simulations and kinetic assays have enabled detailed characterization of the kinetics and pathways of G protein dissociation, a critical event in the GPCR signaling cascade, and the effects of GPCR allosteric modulators.<\/div>\n<\/section>\n<\/div>\n","protected":false},"excerpt":{"rendered":"<p>Congratulations to Jinan and Victor for a new paper published in PNAS on &#8220;Dissociation kinetics of G proteins from G protein\u2013coupled receptors and effects of allosteric modulation&#8220;! Really excited to share this story: The PPI-GaMD method developed earlier by Jinan allowed us to capture the &#8220;very slow&#8221; G protein dissociation from GPCRs, a critical event &hellip; <a href=\"https:\/\/www.med.unc.edu\/pharm\/miaolab\/2025\/11\/new-paper-on-dissociation-kinetics-of-g-proteins\/\" aria-label=\"Read more about New paper on &#8220;Dissociation kinetics of G proteins from G protein\u2013coupled receptors and effects of allosteric modulation&#8221;\">Read more<\/a><\/p>\n","protected":false},"author":115433,"featured_media":0,"comment_status":"closed","ping_status":"closed","sticky":false,"template":"","format":"standard","meta":{"_acf_changed":false,"layout":"","cellInformation":"","apiCallInformation":"","footnotes":"","_links_to":"","_links_to_target":""},"categories":[1],"tags":[],"class_list":["post-3272","post","type-post","status-publish","format-standard","hentry","category-news","odd"],"acf":[],"yoast_head":"<!-- This site is optimized with the Yoast SEO plugin v26.8 - https:\/\/yoast.com\/product\/yoast-seo-wordpress\/ -->\n<title>New paper on &quot;Dissociation kinetics of G proteins from G protein\u2013coupled receptors and effects of allosteric modulation&quot; - Miao Lab<\/title>\n<meta name=\"robots\" content=\"index, follow, max-snippet:-1, max-image-preview:large, max-video-preview:-1\" \/>\n<link rel=\"canonical\" href=\"https:\/\/www.med.unc.edu\/pharm\/miaolab\/2025\/11\/new-paper-on-dissociation-kinetics-of-g-proteins\/\" \/>\n<meta property=\"og:locale\" content=\"en_US\" \/>\n<meta property=\"og:type\" content=\"article\" \/>\n<meta property=\"og:title\" content=\"New paper on &quot;Dissociation kinetics of G proteins from G protein\u2013coupled receptors and effects of allosteric modulation&quot; - Miao Lab\" \/>\n<meta property=\"og:description\" content=\"Congratulations to Jinan and Victor for a new paper published in PNAS on &#8220;Dissociation kinetics of G proteins from G protein\u2013coupled receptors and effects of allosteric modulation&#8220;! Really excited to share this story: The PPI-GaMD method developed earlier by Jinan allowed us to capture the &#8220;very slow&#8221; G protein dissociation from GPCRs, a critical event &hellip; Read more\" \/>\n<meta property=\"og:url\" content=\"https:\/\/www.med.unc.edu\/pharm\/miaolab\/2025\/11\/new-paper-on-dissociation-kinetics-of-g-proteins\/\" \/>\n<meta property=\"og:site_name\" content=\"Miao Lab\" \/>\n<meta property=\"article:published_time\" content=\"2025-11-22T14:43:34+00:00\" \/>\n<meta property=\"article:modified_time\" content=\"2025-12-05T14:54:49+00:00\" \/>\n<meta property=\"og:image\" content=\"https:\/\/www.med.unc.edu\/pharm\/miaolab\/wp-content\/uploads\/sites\/1385\/2025\/11\/PNAS-cover-G-protein-dissociation-white-web.jpg\" \/>\n\t<meta property=\"og:image:width\" content=\"1500\" \/>\n\t<meta property=\"og:image:height\" content=\"1941\" \/>\n\t<meta property=\"og:image:type\" content=\"image\/jpeg\" \/>\n<meta name=\"author\" content=\"Yinglong Miao\" \/>\n<meta name=\"twitter:card\" content=\"summary_large_image\" \/>\n<meta name=\"twitter:label1\" content=\"Written by\" \/>\n\t<meta name=\"twitter:data1\" content=\"Yinglong Miao\" \/>\n\t<meta name=\"twitter:label2\" content=\"Est. reading time\" \/>\n\t<meta name=\"twitter:data2\" content=\"3 minutes\" \/>\n<script type=\"application\/ld+json\" class=\"yoast-schema-graph\">{\"@context\":\"https:\/\/schema.org\",\"@graph\":[{\"@type\":\"Article\",\"@id\":\"https:\/\/www.med.unc.edu\/pharm\/miaolab\/2025\/11\/new-paper-on-dissociation-kinetics-of-g-proteins\/#article\",\"isPartOf\":{\"@id\":\"https:\/\/www.med.unc.edu\/pharm\/miaolab\/2025\/11\/new-paper-on-dissociation-kinetics-of-g-proteins\/\"},\"author\":{\"name\":\"Yinglong Miao\",\"@id\":\"https:\/\/www.med.unc.edu\/pharm\/miaolab\/#\/schema\/person\/2cacef7813a6dc4ea83b7679bf6b9080\"},\"headline\":\"New paper on &#8220;Dissociation kinetics of G proteins from G protein\u2013coupled receptors and effects of allosteric modulation&#8221;\",\"datePublished\":\"2025-11-22T14:43:34+00:00\",\"dateModified\":\"2025-12-05T14:54:49+00:00\",\"mainEntityOfPage\":{\"@id\":\"https:\/\/www.med.unc.edu\/pharm\/miaolab\/2025\/11\/new-paper-on-dissociation-kinetics-of-g-proteins\/\"},\"wordCount\":552,\"image\":{\"@id\":\"https:\/\/www.med.unc.edu\/pharm\/miaolab\/2025\/11\/new-paper-on-dissociation-kinetics-of-g-proteins\/#primaryimage\"},\"thumbnailUrl\":\"https:\/\/www.med.unc.edu\/pharm\/miaolab\/wp-content\/uploads\/sites\/1385\/2025\/11\/PNAS-cover-G-protein-dissociation-white-web-791x1024.jpg\",\"articleSection\":[\"News\"],\"inLanguage\":\"en-US\"},{\"@type\":\"WebPage\",\"@id\":\"https:\/\/www.med.unc.edu\/pharm\/miaolab\/2025\/11\/new-paper-on-dissociation-kinetics-of-g-proteins\/\",\"url\":\"https:\/\/www.med.unc.edu\/pharm\/miaolab\/2025\/11\/new-paper-on-dissociation-kinetics-of-g-proteins\/\",\"name\":\"New paper on \\\"Dissociation kinetics of G proteins from G protein\u2013coupled receptors and effects of allosteric modulation\\\" - 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