Cholesterol-dependent modulation of CD147 transmembrane dimer dynamics: Comparative 150-ns all-atom MD simulations in
Seifeldin Elabed1, Wael M Elshemey2, Medhat Wahba Shafaa1
1Medical Biophysics Division, Physics Department, Faculty of Science, Helwan University, Cairo, Egypt.
Abstract:
Cholesterol is a key organizer of membrane microdomains, yet its quantitative impact on CD147 (Basigin/EMMPRIN) transmembrane (TM) dimerization remains unclear. Here we combine all-atom MD (150 ns, POPC vs POPC:Chol 70:30) with end-point energetics and uncertainty-aware analysis to define a cholesterol-driven lock-and-seal mechanism. In cholesterol, the dimer exhibits more favorable binding thermodynamics (MM/GBSA ΔGbind = -11.21 vs -6.42 kcal mol-1; ΔΔG ≈ -4.79 ± 0.81 kcal mol-1), a ≈3 % reduction in solvent exposure (ΔSASA ≈ -6.2 nm2), and a 10.2 % decrease in interface area (p < 10-15). Inter-protomer H-bond counts increase (+17.8 %) and persist longer (τ: 0.40 → 3.9 ns), while protein-cholesterol contacts are highly persistent (τ ≈ 11.6 ns). Radial distribution functions reveal inward POPC enrichment at the annulus ((r0.5 1.233 → 1.069 nm; g(r) +14-20 %), whereas CHOL-TM contacts remain selective/sparse. Dynamic cross-correlation maps show a 2.8× reduction in mean |C| and ∼99 % loss of strongly correlated pairs, consistent with sterol-induced damping. Critically, HOLE analysis identifies a large aqueous pore in POPC (rfinal ≈ 17.9 Å) that is suppressed in cholesterol (≈2.1 Å). Per-residue MM/GBSA decomposition highlights contiguous hydrophobic arcs (e.g., Val26/Phe27/Leu62/Ala66) and pinning polar pairs (Lys191/Glu73). Convergence diagnostics (block means, ESS-aware CIs) confirm statistical robustness over 150 ns. These results establish how cholesterol compacts, dehydrates, and stabilizes the CD147 dimer and nominate testable hotspots for mutational validation, with implications for raft partitioning, MMP/EGFR signaling, and viral entry pathways.
Insights
Cholesterol significantly stabilizes the CD147 transmembrane dimer by compacting and dehydrating it, a mechanism crucial for cell signaling and viral entry.
Area of Science:
- Membrane biophysics
- Structural biology
- Molecular dynamics
Background:
- Cholesterol organizes membrane microdomains, but its effect on CD147 transmembrane dimerization is not well understood.
- CD147 (Basigin/EMMPRIN) plays roles in cell signaling and viral entry, making its dimerization mechanism important.
Purpose of the Study:
- To quantitatively investigate the impact of cholesterol on CD147 transmembrane dimerization using molecular dynamics simulations.
- To elucidate the cholesterol-driven mechanism stabilizing the CD147 dimer.
Main Methods:
- All-atom molecular dynamics (MD) simulations of CD147 in POPC and POPC:Cholesterol (70:30) lipid bilayers (150 ns).
- End-point energetics (MM/GBSA), solvent accessible surface area (SASA), interface area calculations.
- Analysis of hydrogen bonds, protein-cholesterol contacts, radial distribution functions, and dynamic cross-correlation.
- HOLE analysis for pore identification and per-residue binding free energy decomposition.
Main Results:
- Cholesterol significantly enhances CD147 dimer binding thermodynamics (ΔΔG ≈ -4.79 kcal mol⁻¹).
- Cholesterol reduces dimer solvent exposure and interface area, increases inter-protomer H-bonds, and suppresses aqueous pore formation.
- Cholesterol-induced damping effect observed, with reduced protein dynamics and increased stability (persistent protein-cholesterol contacts).
Conclusions:
- Cholesterol drives a 'lock-and-seal' mechanism that compacts, dehydrates, and stabilizes the CD147 dimer.
- Identified key residues and interactions contributing to cholesterol-mediated stabilization.
- Findings have implications for understanding raft partitioning, MMP/EGFR signaling, and viral entry pathways involving CD147.
