Structure, Flexibility, And Overall Motion Of Transmembrane Peptides Studied By NMR Spectroscopy And Molecular Dynamics Simulations
Bibliographic record
Abstract
Nuclear magnetic resonance (NMR) spectroscopy was used to determine the structure\nof transmembrane (TM) segment IX of the Na+/H+ exchanger isoform 1 (NHE1)\nin dodecylphosphocholine micelles. Studying isolated TM segments in this fashion\nconstitutes a well-established "divide and conquer" approach to the study of membrane\nproteins, which are often extremely difficult to produce, purify, and reconstitute\nin full-length polytopic form. A similar approach was combined with NMR spin relaxation\nexperiments to determine the peptide backbone \nflexibility of NHE1 TM VII.\nThe combined NMR structural and dynamics studies are consistent with an important\nrole for TM segment \nflexibility in the function of NHE1, a protein involved in\napoptosis and myocardial disease. The study of the rhomboid protease system is also\ndescribed from two perspectives: 1) I attempted to produce several TM constructs\nof the substrate spitz or a related construct and the production and purification are\ndescribed in detail; and 2) I present coarse-grained molecular dynamics simulation\nresults for the E. coli rhomboid ecGlpG and a spitz TM construct. Spitz appears to\npreferentially associate with rhomboid near TMs 1 and 3 rather than the proposed\nsubstrate gate at TM 5. The two proteins primarily interact at the termini of helices\nrather than within the hydrocarbon core of the bilayer. Finally, I present a detailed\nanalysis of coarse-grained molecular dynamics simulations of the fibroblast growth\nfactor receptor 3 TM domain dimerization. Specifically, algorithms are described for\nanalyzing critical features of wild-type and G380R mutant constructs. The G380R\nmutation is the cause of achondroplasia, the most common form of human dwarfism.\nThe results suggest that the proximity of a residue to the dimer interface may impact\nthe severity of the mutant phenotype. Strikingly, heterodimer and mutant homodimer\nconstructs exhibit a secondary dimer interface which may explain the increased\nsignaling activity previously reported for the G380R mutation--the helices may rotate\nwith the introduction of G380R. The unifying theme of this work is the 'study\nof membrane proteins' using complementary techniques from structural biology and\ncomputational biochemistry.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.001 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.001 | 0.001 |
| Scholarly communication | 0.000 | 0.001 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.001 | 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 source (direct Gemma or distilled Codex), 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".