Hemoglobin’s β-subunit is primed to synergize oxygen delivery with nitric oxide-mediated increased blood flow
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Bibliographic record
Abstract
Hemoglobin (Hb) undergoes a well-documented R[Formula: see text]T quaternary transition from a high [Formula: see text] affinity R state to a low [Formula: see text] affinity T state to optimize [Formula: see text] delivery to tissues. Also, red blood cells (RBCs) release a nitrovasodilator that increases blood flow to boost [Formula: see text] delivery. Hb’s R[Formula: see text]T transition coordinates its [Formula: see text] desaturation and RBC nitrovasodilator release by much-debated mechanisms. Here we investigate the allosterically controlled [Formula: see text]-nitrosation of Hb at its conserved βCys93 (i.e., SNO-Hb formation) for nitrovasodilator release. First, we examined NO[Formula: see text]/deoxyHb (HbFe II ) incubations following aeration to mimic RBC NO production by the nitrite reductase activity of HbFe II and trapping of the nascent NO by βCys93 to give SNO-Hb on HbFe II conversion to oxyHb (HbFeO 2 ). We confirmed SNO-Hb formation in the incubations with yields modulated by RBC antioxidant enzymes and [Formula: see text] but not CO. Since FeO 2 hemes scavenge free NO, we hypothesized NO channeling within Hb and found by molecular dynamics simulations that most unligated NO molecules placed in the β-distal heme pocket (βDP) rapidly diffuse into a wide β-tunnel connecting the βDP to Hb’s central cavity and βCys93. Contraction of the central cavity brings NO closer to βCys93 in R-state plus βPhe71 and βTyr145 adopt conformations favorable to thiol access and SNO-Hb formation. In T-state, the SNO group is surface-exposed and destabilized to extrude NO. Thus, its structure, dynamics and conserved reactive thiol (βCys93) suggest that the β-subunit evolved to synergize [Formula: see text] and nitrovasoactivity delivery to tissues as a function of Hb [Formula: see text] saturation.
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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 it