Development of enhanced conformational sampling methods to probe the activation landscape of GPCRs

Abrol, Ravinder; Serrano, Erik; Santiago, Luis Jaimes

doi:10.1016/bs.apcsb.2021.11.001

Cited by 3 publications

(2 citation statements)

References 153 publications

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“…Overall, the FES of holo-receptor shows that different agonist binding with GRs produces diverse conformational states of GRs, supporting the hypothesis that conformational rearrangement due to ligand binding regulates GR activation. While the present set of 23 0.1 μs MD trajectories provides a robust comparative data set for binding interactions, future work aided by continuous improvements in supercomputing could aim to generate multimicrosecond to millisecond trajectories to provide replicates for enhanced sampling and statistics and possibly capture also collective large-scale motions triggering activation and allostery. − …”

Section: Resultsmentioning

confidence: 99%

“…While the present set of 23 0.1 μs MD trajectories provides a robust comparative data set for binding interactions, future work aided by continuous improvements in supercomputing could aim to generate multimicrosecond to millisecond trajectories to provide replicates for enhanced sampling and statistics and possibly capture also collective large-scale motions triggering activation and allostery. 92 − 94 …”

Section: Resultsmentioning

confidence: 99%

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Computational Peptide Design Cotargeting Glucagon and Glucagon-like Peptide-1 Receptors

Vishnoi,

Bhattacharya,

Walsh

et al. 2023

J. Chem. Inf. Model.

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Peptides are sustainable alternatives to conventional therapeutics for G protein-coupled receptor (GPCR) linked disorders, promising biocompatible and tailorable next-generation therapeutics for metabolic disorders including type-2 diabetes, as agonists of the glucagon receptor (GCGR) and the glucagon-like peptide-1 receptor (GLP-1R). However, single agonist peptides activating GLP-1R to stimulate insulin secretion also suppress obesity-linked glucagon release. Hence, bioactive peptides cotargeting GCGR and GLP-1R may remediate the blood glucose and fatty acid metabolism imbalance, tackling both diabetes and obesity to supersede current monoagonist therapy. Here, we design and model optimized peptide sequences starting from peptide sequences derived from earlier phage-displayed library screening, identifying those with predicted molecular binding profiles for dual agonism of GCGR and GLP-1R. We derive design rules from extensive molecular dynamics simulations based on peptide−receptor binding. Our newly designed coagonist peptide exhibits improved predicted coupled binding affinity for GCGR and GLP-1R relative to endogenous ligands and could in the future be tested experimentally, which may provide superior glycemic and weight loss control.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Computational Peptide Design Cotargeting Glucagon and Glucagon-like Peptide-1 Receptors

Vishnoi,

Bhattacharya,

Walsh

et al. 2023

J. Chem. Inf. Model.

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Agonist activation to open the Gα subunit of the GPCR–G protein precoupled complex defines functional agonist activation of TAS2R5

Young Yang,

Duy Mac,

Strzelinski

et al. 2024

Proc. Natl. Acad. Sci. U.S.A.

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G protein-coupled receptors (GPCRs) regulate multiple cellular responses and represent highly successful therapeutic targets. The mechanisms by which agonists activate the G protein are unclear for many GPCR families, including the bitter taste receptors (TAS2Rs). We ascertained TAS2R5 properties by live cell-based functional assays, direct binding affinity measurements using optical resonators, and atomistic molecular dynamics simulations. We focus on three agonists that exhibit a wide range of signal transduction in cells despite comparable ligand–receptor binding energies derived from direct experiment and computation. Metadynamics simulations revealed that the critical barrier to activation is ligand-induced opening of the G protein between the α-helical (AH) and Ras-like domains of Gα subunit from a precoupled TAS2R5-G protein state to the fully activated state. A moderate agonist opens the AH-Ras cleft from 22 Å to 31 Å with an energy gain of −4.8 kcal mol −1 , making GDP water-exposed for signaling. A high-potency agonist had an energy gain of −11.1 kcal mol −1 . The low-potency agonist is also exothermic for Gα opening, but with an energy gain of only −1.4 kcal mol −1 . This demonstrates that TAS2R5 agonist-bound functional potencies are derived from energy gains in the transition from a precoupled complex at the level of Gα opening. Our experimental and computational study provides insights into the activation mechanism of signal transduction that provide a basis for rational design of new drugs.

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Metadynamics simulations leveraged by statistical analyses and artificial intelligence-based tools to inform the discovery of G protein-coupled receptor ligands

Fiorillo

Filizola

2022

Front. Endocrinol.

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G Protein-Coupled Receptors (GPCRs) are a large family of membrane proteins with pluridimensional signaling profiles. They undergo ligand-specific conformational changes, which in turn lead to the differential activation of intracellular signaling proteins and the consequent triggering of a variety of biological responses. This conformational plasticity directly impacts our understanding of GPCR signaling and therapeutic implications, as do ligand-specific kinetic differences in GPCR-induced transducer activation/coupling or GPCR-transducer complex stability. High-resolution experimental structures of ligand-bound GPCRs in the presence or absence of interacting transducers provide important, yet limited, insights into the highly dynamic process of ligand-induced activation or inhibition of these receptors. We and others have complemented these studies with computational strategies aimed at characterizing increasingly accurate metastable conformations of GPCRs using a combination of metadynamics simulations, state-of-the-art algorithms for statistical analyses of simulation data, and artificial intelligence-based tools. This minireview provides an overview of these approaches as well as lessons learned from them towards the identification of conformational states that may be difficult or even impossible to characterize experimentally and yet important to discover new GPCR ligands.

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Development of enhanced conformational sampling methods to probe the activation landscape of GPCRs

Cited by 3 publications

References 153 publications

Computational Peptide Design Cotargeting Glucagon and Glucagon-like Peptide-1 Receptors

Computational Peptide Design Cotargeting Glucagon and Glucagon-like Peptide-1 Receptors

Agonist activation to open the Gα subunit of the GPCR–G protein precoupled complex defines functional agonist activation of TAS2R5

Metadynamics simulations leveraged by statistical analyses and artificial intelligence-based tools to inform the discovery of G protein-coupled receptor ligands

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