ArticleJournal of chemical information and modeling2024
Elucidating Dynamics of Adenylate Kinase from Enzyme Opening to Ligand Release.
Article in Journal of chemical information and modeling, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 9 papers.
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Who cites it
9 citing papers in PubMed, 10 citations in OpenAlex.
- Methods for the establishment of enzymatic mechanisms - from QM to ML.Chemical science · 2026Review
- Real-time Structural Tracking of Slow P-type ATPase Dynamics.The Journal of membrane biology · 2026Article
- Generation of Pathway Signatures by Combining Normal Modes with Weighted Ensemble Simulations.bioRxiv : the preprint server for biology · 2026Article
- Article
- Toward the Prediction of Binding Events in Very Flexible, Allosteric, Multidomain Proteins.Journal of chemical information and modeling · 2025Article
- Predicting binding events in very flexible, allosteric, multi-domain proteins.bioRxiv : the preprint server for biology · 2024Article
- Enzyme activation by urea reveals the interplay between conformational dynamics and substrate binding: a single-molecule FRET study.bioRxiv : the preprint server for biology · 2024Article
- Magnesium induced structural reorganization in the active site of adenylate kinase.Science advances · 2024Article
- Perspectives on Computational Enzyme Modeling: From Mechanisms to Design and Drug Development.ACS omega · 2024Review
Corrections and comments
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Authors and funding
5 authors at 2 institutions in 2 countries.
Funding
Abstract
This study explores ligand-driven conformational changes in adenylate kinase (AK), which is known for its open-to-close conformational transitions upon ligand binding and release. By utilizing string free energy simulations, we determine the free energy profiles for both enzyme opening and ligand release and compare them with profiles from the apoenzyme. Results reveal a three-step ligand release process, which initiates with the opening of the adenosine triphosphate-binding subdomain (ATP lid), followed by ligand release and concomitant opening of the adenosine monophosphate-binding subdomain (AMP lid). The ligands then transition to nonspecific positions before complete dissociation. In these processes, the first step is energetically driven by ATP lid opening, whereas the second step is driven by ATP release. In contrast, the AMP lid opening and its ligand release make minor contributions to the total free energy for enzyme opening. Regarding the ligand binding mechanism, our results suggest that AMP lid closure occurs via an induced-fit mechanism triggered by AMP binding, whereas ATP lid closure follows conformational selection. This difference in the closure mechanisms provides an explanation with implications for the debate on ligand-driven conformational changes of AK. Additionally, we determine an X-ray structure of an AK variant that exhibits significant rearrangements in the stacking of catalytic arginines, explaining its reduced catalytic activity. In the context of apoenzyme opening, the sequence of events is different. Here, the AMP lid opens first while the ATP lid remains closed, and the free energy associated with ATP lid opening varies with orientation, aligning with the reported AK opening and closing rate heterogeneity. Finally, this study, in conjunction with our previous research, provides a comprehensive view of the intricate interplay between various structural elements, ligands, and catalytic residues that collectively contribute to the robust catalytic power of the enzyme.
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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.