ArticleJournal of the American Chemical Society2016
Conformational Changes in the Epidermal Growth Factor Receptor: Role of the Transmembrane Domain Investigated by Coarse-Grained MetaDynamics Free Energy Calculations.
Article in Journal of the American Chemical Society, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 64 papers.
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Who cites it
64 citing papers in PubMed, 136 citations in OpenAlex.
- Uncovering the biological mechanisms of TREM2 with molecular simulations: A comprehensive review and perspective.Progress in biophysics and molecular biology · 2026Review
- The SIMDA framework maps PIP2-binding sites regulating the KCNQ1 channel.Nature communications · 2026Article
- Integrative structural and dynamics studies of epidermal growth factor receptor (EGFR).Experimental & molecular medicine · 2026Review
- Article
- EGFR Mutations and Tyrosine Kinase Inhibitors: Structural Insights and Therapeutic Advances.ACS omega · 2026Review
- Deciphering the Structural Basis of Allosteric Inhibition of Mutant Epidermal Growth Factor Receptor and Identification of Novel Inhibitors.Computational and structural biotechnology journal · 2026Article
- Active regulation of the epidermal growth factor receptor by the membrane bilayer.bioRxiv : the preprint server for biology · 2025Article
- EGFR: New Insights on Its Activation and Mutation in Tumor and Tumor Immunotherapy.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Review
- Thermodynamics and Kinetics of the Deintercalation of a Novel Anthracycline from Double-Stranded Oligonucleotide DNA.The journal of physical chemistry. B · 2025Article
- Cholesterol-dependent dimerization and conformational dynamics of EphA2 receptors from coarse-grained and all-atom simulations.Structure (London, England : 1993) · 2025Article
- Simulation of Neurotrophin Receptor Transmembrane Helix Interactions Reveals Active States and Distinct Signaling Mechanisms.JACS Au · 2025Article
- The Influence of Phosphoinositide Lipids in the Molecular Biology of Membrane Proteins: Recent Insights from Simulations.Journal of molecular biology · 2025Review
- Integration of molecular coarse-grained model into geometric representation learning framework for protein-protein complex property prediction.Nature communications · 2024Article
- Machine Learning Derived Collective Variables for the Study of Protein Homodimerization in Membrane.Journal of chemical theory and computation · 2024Article
- Drug-resistant EGFR mutations promote lung cancer by stabilizing interfaces in ligand-free kinase-active EGFR oligomers.Nature communications · 2024Article
- Targeting EGFR with molecular degraders as a promising strategy to overcome resistance to EGFR inhibitors.Future medicinal chemistry · 2024Review
- T-cell virtuosity in ''knowing thyself".Frontiers in immunology · 2024Review
- Structural basis of dimerization of chemokine receptors CCR5 and CXCR4.Nature communications · 2023Article
- The role of structural heterogeneity in the homodimerization of transmembrane proteins.The Journal of chemical physics · 2023Article
- How Neuromembrane Lipids Modulate Membrane Proteins: Insights from G-Protein-Coupled Receptors (GPCRs) and Receptor Tyrosine Kinases (RTKs).Cold Spring Harbor perspectives in biology · 2023Review
4 more citing papers are in PubMed but not listed here.
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Authors and funding
3 authors at 2 institutions in 3 countries.
Funding
Abstract
The epidermal growth factor receptor (EGFR) is a dimeric membrane protein that regulates key aspects of cellular function. Activation of the EGFR is linked to changes in the conformation of the transmembrane (TM) domain, brought about by changes in interactions of the TM helices of the membrane lipid bilayer. Using an advanced computational approach that combines Coarse-Grained molecular dynamics and well-tempered MetaDynamics (CG-MetaD), we characterize the large-scale motions of the TM helices, simulating multiple association and dissociation events between the helices in membrane, thus leading to a free energy landscape of the dimerization process. The lowest energy state of the TM domain is a right-handed dimer structure in which the TM helices interact through the N-terminal small-X3-small sequence motif. In addition to this state, which is thought to correspond to the active form of the receptor, we have identified further low-energy states that allow us to integrate with a high level of detail a range of previous experimental observations. These conformations may lead to the active state via two possible activation pathways, which involve pivoting and rotational motions of the helices, respectively. Molecular dynamics also reveals correlation between the conformational changes of the TM domains and of the intracellular juxtamembrane domains, paving the way for a comprehensive understanding of EGFR signaling at the cell membrane.
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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.