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.
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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.
