ArticleProceedings of the National Academy of Sciences of the United States of America2016
Transition path theory analysis of c-Src kinase activation.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2016. 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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41 citing papers in PubMed.
- An Expanded Markov State Model-Transition Path Theory Framework for Ion Conduction Reactive Pathways through Membrane Channels.The journal of physical chemistry letters · 2026Article
- De novo Folding Mechanisms of Lasso Peptides.bioRxiv : the preprint server for biology · 2026Article
- Following the Committor Flow: A Data-Driven Discovery of Transition Pathways.Journal of chemical theory and computation · 2026Article
- Unsupervised synchronization of molecular dynamics trajectories via graph embedding and time warping.Bioinformatics (Oxford, England) · 2026Article
- Topological Analysis Reveals Multiple Pathways in Molecular Dynamics.Journal of chemical theory and computation · 2025Article
- Cyclopamine modulates smoothened receptor activity in a binding position dependent manner.Communications biology · 2024Article
- Unveiling Allosteric Regulation and Binding Mechanism of BRD9 through Molecular Dynamics Simulations and Markov Modeling.Molecules (Basel, Switzerland) · 2024Article
- Identification of a Cryptic Pocket in Methionine Aminopeptidase-II Using Adaptive Bandit Molecular Dynamics Simulations and Markov State Models.ACS omega · 2024Article
- sciCSR infers B cell state transition and predicts class-switch recombination dynamics using single-cell transcriptomic data.Nature methods · 2024Article
- Binding Position Dependent Modulation of Smoothened Activity by Cyclopamine.bioRxiv : the preprint server for biology · 2024Article
- An Efficient Path Classification Algorithm Based on Variational Autoencoder to Identify Metastable Path Channels for Complex Conformational Changes.Journal of chemical theory and computation · 2023Article
- Inexact iterative numerical linear algebra for neural network-based spectral estimation and rare-event prediction.The Journal of chemical physics · 2023Article
- Molecular Dynamics Simulations Combined with Markov Model to Explore the Effect of Allosteric Inhibitor Binding on Bromodomain-Containing Protein 4.International journal of molecular sciences · 2023Article
- Protein Flexibility and Dissociation Pathway Differentiation Can Explain Onset of Resistance Mutations in Kinases.Angewandte Chemie (International ed. in English) · 2022Article
- Pre-exascale HPC approaches for molecular dynamics simulations. Covid-19 research: A use case.Wiley interdisciplinary reviews. Computational molecular science · 2022Article
- Mechanical force can enhance c-Src kinase activity by impairing autoinhibition.Biophysical journal · 2022Article
- Allosteric regulation of autoinhibition and activation of c-Abl.Computational and structural biotechnology journal · 2022Article
- Energy landscape of the SARS-CoV-2 reveals extensive conformational heterogeneity.Current research in structural biology · 2022Article
- TYROSINE KINASES: COMPLEX MOLECULAR SYSTEMS CHALLENGING COMPUTATIONAL METHODOLOGIES.The European physical journal. B · 2021Article
- Markov State Models and Molecular Dynamics Simulations Provide Understanding of the Nucleotide-Dependent Dimerization-Based Activation of LRRK2 ROC Domain.Molecules (Basel, Switzerland) · 2021Article
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4 authors.
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Abstract
Nonreceptor tyrosine kinases of the Src family are large multidomain allosteric proteins that are crucial to cellular signaling pathways. In a previous study, we generated a Markov state model (MSM) to simulate the activation of c-Src catalytic domain, used as a prototypical tyrosine kinase. The long-time kinetics of transition predicted by the MSM was in agreement with experimental observations. In the present study, we apply the framework of transition path theory (TPT) to the previously constructed MSM to characterize the main features of the activation pathway. The analysis indicates that the activating transition, in which the activation loop first opens up followed by an inward rotation of the αC-helix, takes place via a dense set of intermediate microstates distributed within a fairly broad "transition tube" in a multidimensional conformational subspace connecting the two end-point conformations. Multiple microstates with negligible equilibrium probabilities carry a large transition flux associated with the activating transition, which explains why extensive conformational sampling is necessary to accurately determine the kinetics of activation. Our results suggest that the combination of MSM with TPT provides an effective framework to represent conformational transitions in complex biomolecular systems.
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