Bibliographic record
Abstract
Due to the challenges of insolubility, aggregation, and purification presented by membrane proteins in structure determination, it is important to develop alternative methods for elucidating their final folds. In particular, since few membrane protein high-resolution structures are available, it would be of value to be able to predict the three-dimensional conformation arising from the transmembrane (TM) helical segment(s) of a membrane protein largely on the basis of the protein primary sequence. In order to predict this structure and its stability, it is necessary to evaluate the principal energetic contributions in the folding process, including helix-helix, helix-lipid, and lipid-lipid interactions. To this end, this thesis examines sequence motifs and packing interactions both between TM helices, and between the TM helix and the lipid acyl chains of the surrounding phospholipid bilayer. By using a de novo designed hydrophobic hairpin as a model, it was found that helix-helix association exists as a delicate balance of forces consisting predominantly of electrostatic and van der Waals interactions. In situations where hydrophobic van der Waals packing energy between helices is sufficient to prevent significant rotation about the major axes of interacting helices, we found that intra-hairpin side chain - side chain hydrogen bond formation occurred mainly when pairs of polar residues were interfacially located and proximal. The role of lipid in helix-helix associations was also addressed; we showed a strong inverse correlation between non-polar group lipid accessibility and dimer affinity in both glycophonn A (GpA) and M13 coat protein (MCP) Gly-xxx-Gly (GG4) motif-mediated homodimers, suggesting that lipid can act as a poor membrane protein solvent---conceptually analogous to water in soluble protein folding---and thus can contribute to dimer stability. In a further study of both GpA and MCP homodimers, we demonstrated that centrally located GG4 motifs are capable of stronger helix-helix interactions than those proximal to TM helix ends even while surrounding interfacial residues are maintained, indicating that relative importance of the TM context of GG4 motifs in stabilizing helix-helix interactions. These overall findings are interpreted in terms of progress toward prediction of helix-helix interaction strength in the folding and assembly of membrane proteins.
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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 | 0.000 |
| 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) | 0.002 | 0.001 |
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".