Structural insights into the ATP-dependent activation of NOD-like receptor with pyrin 3 (NLRP3) protein by molecular dynamics simulation
Bibliographic record
Abstract
The inflammasome-forming NOD-like receptor containing pyrin-3 (NLRP3) protein is a critical player in the innate immune responses to cellular danger signals. New structural data of NLRP3 provide a framework to probe the conformational impact of nucleotide binding. In this study, microsecond molecular dynamics (MD) simulations were used to detail information on the unique structural conformations adopted by NLRP3 with ATP or ADP binding. Sampling convergence reflected a high degree of confidence in the MD simulations as shown by RMSD and protein-nucleotide concordance, favourable overall MM-PBSA ligand binding energies for both nucleotides and low cosine coefficients of the principal eigenvectors obtained with essential dynamics (ED) analysis. NLRP3-ADP simulations provide relatively stable conformations with few global rearrangements as shown by decreased protein RMSD, Rg, SASA, and solvent accessibility for the ADP-bound structure. In contrast, ATP binding induced increased flexibility and resulted in substantive conformational changes to the NLRP3 structure. Binding of ATP was thermodynamically favourable as shown by the ΔGsolv and MM-PBSA calculations of complex free energies, and these NLRP3-ATP simulations resulted in similar structural transitions as observed in the activated NLRC4 empirical structure. Lastly, the active conformation of NLRP3 critically depends on hinging between the HD2 and LRR domains, whereby ATP binding drives local conformational changes that are conveyed to the global structure.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".