Coarse-grained molecular dynamics simulations of lipid-protein interactions in SLC4 proteins
Bibliographic record
Abstract
Abstract The SLC4 family of secondary bicarbonate transporters is responsible for the transport of HCO 3 −, CO 3 2− , Cl − , Na + , K + , NH 3 and H + necessary for regulation of pH and ion homeostasis. They are widely expressed in numerous tissues throughout the body and function in different cell types with different membrane properties. Potential lipid roles in SLC4 function have been reported in experimental studies, focusing mostly on two members of the family: AE1 (Cl − /HCO 3 − exchanger) and NBCe1 (Na + -CO 3 2− cotransporter). Previous computational studies of the outward facing (OF) state of AE1 with model lipid membranes revealed enhanced protein-lipid interactions between cholesterol (CHOL) and phosphatidylinositol bisphosphate (PIP2). However, the protein-lipid interactions in other members of the family and other conformation states are still poorly understood and this precludes the detailed studies of a potential regulatory role for lipids in the SLC4 family. In this work, we performed multiple 50 µs coarse-grained molecular dynamics simulations on three members of the SLC4 family with different transport modes: AE1, NBCe1 and NDCBE (a Na + -CO 3 2− /Cl − exchanger), in model HEK293 membranes consisting of CHOL, PIP2, phosphatidylcholine (POPC), phosphatidylethanolamine (POPE), phosphatidylserine (POPS), and sphingomyelin (POSM). The recently resolved inward-facing (IF) state of AE1 was also included in the simulations. Lipid-protein contact analysis of the simulated trajectories was performed with the ProLint server, which provides a multitude of visualization tools for illustration of areas of enhanced lipid-protein contact and identification of putative lipid binding sites within the protein matrix. We observed enrichment of CHOL and PIP2 around all proteins with subtle differences in their distribution depending on the protein type and conformation state. Putative binding sites were identified for CHOL, PIP2, POPC, and POSM in the three studied proteins and their potential roles in the SLC4 transport function, conformational transition and protein dimerization were discussed. Statement of significance The SLC4 protein family is involved in critical physiological processes like pH and blood pressure regulation and maintenance of ion homeostasis. Its members can be found in various tissues. A number of studies suggest possible lipid regulation of the SLC4 function. However, the protein-lipid interactions in the SLC4 family are still poorly understood. Here we make use of long coarse-grained molecular dynamics simulations to assess the protein-lipid interactions in three SLC4 proteins with different transport modes, AE1, NBCe1, and NDCBE. We identify putative lipid binding sites for several lipid types of potential mechanistic importance, discuss them in the framework of the known experimental data and provide a necessary basis for further studies on lipid regulation of SLC4 function.
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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 | 0.001 | 0.003 |
| Meta-epidemiology (narrow) | 0.001 | 0.001 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.002 | 0.002 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.002 | 0.001 |
| Research integrity | 0.002 | 0.002 |
| Insufficient payload (model declined to judge) | 0.004 | 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".