ArticleThe journal of physical chemistry. B2015
Computational study of the "DFG-flip" conformational transition in c-Abl and c-Src tyrosine kinases.
Article in The journal of physical chemistry. B, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 41 papers.
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Who cites it
41 citing papers in PubMed.
- Tyrosine kinases sample unique activation ensembles.bioRxiv : the preprint server for biology · 2026Article
- DyVarMap: Integrating Conformational Dynamics and Interpretable Machine Learning for Cancer-Associated Missense Variant Classification in FGFR2.Bioengineering (Basel, Switzerland) · 2026Article
- Weighted Ensemble Simulations With the Drude Polarizable Model.Journal of computational chemistry · 2025Article
- FastConformation: A Standalone ML-Based Toolkit for Modeling and Analyzing Protein Conformational Ensembles at Scale.bioRxiv : the preprint server for biology · 2025Article
- Prospective Evaluation of Structure-Based Simulations Reveal Their Ability to Predict the Impact of Kinase Mutations on Inhibitor Binding.The journal of physical chemistry. B · 2025Article
- Prospective evaluation of structure-based simulations reveal their ability to predict the impact of kinase mutations on inhibitor binding.bioRxiv : the preprint server for biology · 2025Article
- Improving docking and virtual screening performance using AlphaFold2 multi-state modeling for kinases.Scientific reports · 2024Article
- CHARMM at 45: Enhancements in Accessibility, Functionality, and Speed.The journal of physical chemistry. B · 2024Review
- Exploring Kinase Asp-Phe-Gly (DFG) Loop Conformational Stability with AlphaFold2-RAVE.Journal of chemical information and modeling · 2024Article
- Classifying protein kinase conformations with machine learning.Protein science : a publication of the Protein Society · 2024Article
- Perspectives on Computational Enzyme Modeling: From Mechanisms to Design and Drug Development.ACS omega · 2024Review
- Article
- Molecular Simulations of Conformational Transitions within the Insulin Receptor Kinase Reveal Consensus Features in a Multistep Activation Pathway.The journal of physical chemistry. B · 2023Article
- Protein Flexibility and Dissociation Pathway Differentiation Can Explain Onset of Resistance Mutations in Kinases.Angewandte Chemie (International ed. in English) · 2022Article
- A Companion Guide to the String Method with Swarms of Trajectories: Characterization, Performance, and Pitfalls.Journal of chemical theory and computation · 2022Article
- Practical Protocols for Efficient Sampling of Kinase-Inhibitor Binding Pathways Using Two-Dimensional Replica-Exchange Molecular Dynamics.Frontiers in molecular biosciences · 2022Article
- Allosteric regulation of autoinhibition and activation of c-Abl.Computational and structural biotechnology journal · 2022Article
- Activation of Abl1 Kinase Explored Using Well-Tempered Metadynamics Simulations on an Essential Dynamics Sampled Path.Journal of chemical theory and computation · 2021Article
- TYROSINE KINASES: COMPLEX MOLECULAR SYSTEMS CHALLENGING COMPUTATIONAL METHODOLOGIES.The European physical journal. B · 2021Article
- Multiscale computational study of ligand binding pathways: Case of p38 MAP kinase and its inhibitors.Biophysical journal · 2021Article
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Authors and funding
3 authors.
Funding
Abstract
Protein tyrosine kinases are crucial to cellular signaling pathways regulating cell growth, proliferation, metabolism, differentiation, and migration. To maintain normal regulation of cellular signal transductions, the activities of tyrosine kinases are also highly regulated. The conformation of a three-residue motif Asp-Phe-Gly (DFG) near the N-terminus of the long "activation" loop covering the catalytic site is known to have a critical impact on the activity of c-Abl and c-Src tyrosine kinases. A conformational transition of the DFG motif can switch the enzyme from an active (DFG-in) to an inactive (DFG-out) state. In the present study, the string method with swarms-of-trajectories was used to computationally determine the reaction pathway connecting the two end-states, and umbrella sampling calculations were carried out to characterize the thermodynamic factors affecting the conformations of the DFG motif in c-Abl and c-Src kinases. According to the calculated free energy landscapes, the DFG-out conformation is clearly more favorable in the case of c-Abl than that of c-Src. The calculations also show that the protonation state of the aspartate residue in the DFG motif strongly affects the in/out conformational transition in c-Abl, although it has a much smaller impact in the case of c-Src due to local structural differences.
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