V600E biases the BRAF kinase domain toward an activation-compatible conformational ensemble through long-range dynamic rewiring.

Overview

1. College of Agriculture and Biological Science, Dali University, Dali 671000, China
2. Key Laboratory of Bioinformatics and Computational Biology of the Department of Education of Yunnan Province, Dali University, Dali 671000, China
3. Co-Innovation Center for Cangshan Mountain and Erhai Lake Integrated Protection and Green Development of Yunnan Province, Dali University, Dali 671000, China

Abstract

How oncogenic mutations reshape kinase conformational ensembles to favor aberrant signaling remains incompletely understood. Here, we combined microsecond-scale molecular dynamics simulations, Markov state models, and neural relational inference to investigate how the V600E mutation remodels the dynamics of the inactive-like, nucleotide-bound BRAF kinase domain. V600E did not produce a single fully active conformation but instead biased the kinase toward an activation-compatible conformational ensemble. MSM analysis revealed pronounced enrichment of a dominant metastable state, S3, characterized by a shortened Lys483–Glu501 Cα–Cα distance and a more inward αC-helix arrangement. This mutation-enriched state was kinetically stabilized, as indicated by prolonged mean first passage times for transitions from S3 to the minor states. At the dynamic-network level, V600E reorganized long-range coordination among the P-loop, αC-helix, activation loop, and distal flexible regions and altered preferred model-inferred communication routes connecting these regulatory elements. Together, these results support a model in which V600E preorganizes the inactive-like BRAF kinase domain toward activation-compatible conformations through conformational reweighting and long-range dynamic rewiring. Such conformational preorganization may facilitate oncogenic signaling in the presence of the additional regulatory interactions required for complete kinase activation.

Reproduced under the paper's license (CC BY-NC), from the paper cited above.

Code

The paper links to its data, not to its authors' code: see the Data section.

Tracing map

A tracing map links a paper to the code its authors published: this paper has none, so it has no map.

Data

Datasets cited

• zenodo:21329236 — at Zenodo; found in “Data availability”

Data availability

The experimental data and molecular dynamics simulation trajectories used in this study have been made publicly available in the Zenodo database at the following access link: https://doi.org/10.5281/zenodo.21329236.

Supplementary information (SI) is available. See DOI: https://doi.org/10.1039/d6ra04733e.

Reproduced under the paper's license (CC BY-NC), from the paper cited above.

Versions

The history of this record: each version stored by the harvester or made by a correction of its authors or of the maintainers of its code, and what changed in its facts. The texts of the paper (its abstract, its availability statements) are not part of it; versions that changed only those are not listed.

Version 1, 27 September 2026: the first record

Recorded: type, language, journal, volume, issue, pages, dates, 6 authors, 1 funder, 42 references.

Cite

This paper

Zhang, B.-D., Xi, Q., Ying, Y.-M., Zhao, D.-R., Yang, L.-Q., & Sang, P. (2026). V600E biases the BRAF kinase domain toward an activation-compatible conformational ensemble through long-range dynamic rewiring. RSC advances, 16(40), 46674-46689. https://doi.org/10.1039/d6ra04733e

Similar papers

The papers with a page that share the most with this one: the tools found in their code, their categories, datasets, cited references and authors, the rarest counting most.

[1] doi:10.1038/s41467-026-75444-4 [code]

Structural insights enable drug discovery for the neuronal NBCn2 carbonate transporter.

Journal: Nature communications

In common: cellular / molecular, 5 references

[2] doi:10.1038/s41467-026-75306-z

Substrate recognition and transport mechanism of the human proton-coupled amino-acid transporter 1 (SLC36A1).

Journal: Nature communications

In common: cellular / molecular, 3 references

[3] doi:10.1083/jcb.202509110

The missing link: Piccolino is essential for tethering synaptic vesicles to rod photoreceptor ribbons.

Journal: The Journal of cell biology

In common: cellular / molecular, 3 references

[4] doi:10.1021/acsomega.5c13203

Investigating the Function of C‑Terminal Tails of Human Tubulin Isotypes in the Motility Regulation of Cytoplasmic Dynein.

Journal: ACS omega

In common: cellular / molecular, 3 references

[5] doi:10.1186/s13073-026-01699-7

De novo variants in NPTN cause a neurodevelopmental disorder with autism and neuroplastin-PMCA hypofunction.

Journal: Genome medicine

In common: 3 references

[6] doi:10.1038/s41467-026-71619-1

Structurally exclusive Teneurin complexes orchestrate divergent programs in early cortical development.

Journal: Nature communications

In common: 3 references

[7] doi:10.1016/j.isci.2026.117147 [code]

Penetrating potential evaluation of cyclotriphosphazenes target blood-brain barrier via computational toxicology methods.

Journal: iScience

In common: 3 references

[8] doi:10.1038/s41565-026-02180-7 [code]

Intracellular neuronal recordings across DNA tiles.

Journal: Nature nanotechnology

In common: cellular / molecular, 2 references

[9] doi:10.1038/s41594-026-01789-5 [code]

Calcium dependent activation of the TMEM16F scramblase and ion channel.

Journal: Nature structural & molecular biology

In common: cellular / molecular, 2 references

[10] doi:10.1038/s41467-026-74888-y

Engineered zwitterion-nanodelivery for precision targeting of brain metastases.

Journal: Nature communications

In common: 2 references

Contribute

The authors of this paper can claim it, correct its record and validate its tracing map, and the maintainers of its code (its owner, or a public member of its organization) correct what it says of their repository; anyone signed in can ask for its removal. Every request goes to OSCR's own machine, which answers it; your account page follows them.

Request its removal

To ask OSCR to remove this record, the copies of its authors' scripts or its tracing map, use the removal request page: signed in, you say who you are, what to remove and why, then review and confirm the request. Published rules decide every request (how).

Discussion: questions and error reports about this paper and its code, from signed-in readers and its authors. It opens with sign-in.

Reproductions: reports from readers who ran the authors' code: what they reproduced, with which environment, commit and data. It opens with sign-in.

Activity: what happens around this paper: new versions of its record, its map's validation, discussions and reproductions. It opens with sign-in.