ArticlePLoS computational biology2011
Ligand-induced modulation of the free-energy landscape of G protein-coupled receptors explored by adaptive biasing techniques.
Article in PLoS computational biology, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 51 papers.
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Who cites it
51 citing papers in PubMed, 96 citations in OpenAlex.
- Mechanisms and Manifestations of Ligand Bias in Signaling: Focus on Receptor Tyrosine Kinases.Chemical reviews · 2026Review
- A Transferable and Robust Computational Framework for Class A GPCR Activation Free Energies.The journal of physical chemistry letters · 2026Article
- Enhanced Sampling and Tailored Collective Variables Yield Reproducible Free Energy Landscapes of Beta-1 Adrenergic Receptor Activation.Journal of chemical theory and computation · 2025Article
- Path-Based Nonequilibrium Binding Free Energy Estimation, from Protein-Ligand to RNA-Ligand Binding.Journal of chemical information and modeling · 2025Article
- In search of a photoswitchable drug for serotonin receptors: a molecular dynamics simulation study.RSC advances · 2025Article
- Molecular simulations reveal intricate coupling between agonist-bound β-adrenergic receptors and G protein.iScience · 2025Article
- Systematic analysis of biomolecular conformational ensembles with PENSA.The Journal of chemical physics · 2025Article
- Hidden water's influence on rhodopsin activation.Biophysical journal · 2024Review
- Minute-timescale free-energy calculations reveal a pseudo-active state in the adenosine AChem · 2024Article
- Mechanical stress and anionic lipids synergistically stabilize an atypical structure of the angiotensin II type 1 receptor (AT1).PLoS computational biology · 2024Article
- Coevolution-Driven Method for Efficiently Simulating Conformational Changes in Proteins Reveals Molecular Details of Ligand Effects in the β2AR Receptor.The journal of physical chemistry. B · 2023Article
- Flexible Topology: A Dynamic Model of a Continuous Chemical Space.Journal of chemical theory and computation · 2023Article
- GLOW: A Workflow Integrating Gaussian-Accelerated Molecular Dynamics and Deep Learning for Free Energy Profiling.Journal of chemical theory and computation · 2022Article
- Metadynamics simulations leveraged by statistical analyses and artificial intelligence-based tools to inform the discovery of G protein-coupled receptor ligands.Frontiers in endocrinology · 2022Review
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- Structure based prediction of a novel GPR120 antagonist based on pharmacophore screening and molecular dynamics simulations.Computational and structural biotechnology journal · 2021Article
- G-Protein coupled receptors: structure and function in drug discovery.RSC advances · 2020Review
- Energy Landscapes Reveal Agonist Control of G Protein-Coupled Receptor Activation via Microswitches.Biochemistry · 2020Article
- Free energy calculations of the functional selectivity of 5-HT2B G protein-coupled receptor.PloS one · 2020Article
Corrections and comments
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Authors and funding
5 authors at 1 institution in 1 country.
Funding
Abstract
Extensive experimental information supports the formation of ligand-specific conformations of G protein-coupled receptors (GPCRs) as a possible molecular basis for their functional selectivity for signaling pathways. Taking advantage of the recently published inactive and active crystal structures of GPCRs, we have implemented an all-atom computational strategy that combines different adaptive biasing techniques to identify ligand-specific conformations along pre-determined activation pathways. Using the prototypic GPCR β2-adrenergic receptor as a suitable test case for validation, we show that ligands with different efficacies (either inverse agonists, neutral antagonists, or agonists) modulate the free-energy landscape of the receptor by shifting the conformational equilibrium towards active or inactive conformations depending on their elicited physiological response. Notably, we provide for the first time a quantitative description of the thermodynamics of the receptor in an explicit atomistic environment, which accounts for the receptor basal activity and the stabilization of different active-like states by differently potent agonists. Structural inspection of these metastable states reveals unique conformations of the receptor that may have been difficult to retrieve experimentally.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.