Cholesterol-dependent modulation of CD147 transmembrane dimer dynamics: Comparative 150-ns all-atom MD simulations in...

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.