Molecular dynamics simulation reveals CETP forms a more flexible structure in solution than in the crystal, supporting a continuous internal tunnel (Proteins 2012)

Cholesteryl ester transfer protein (CETP) mediates the net transfer of cholesteryl esters (CEs) from atheroprotective high-density lipoproteins (HDLs) to atherogenic low-density lipoproteins (LDLs) or very-low-density lipoproteins (VLDLs). Inhibition of CETP raises HDL cholesterol (good cholesterol) levels and reduces LDL cholesterol (bad cholesterol) levels, making it a promising drug target for the prevention and treatment of coronary heart disease. Although the crystal structure of CETP has been determined, the molecular mechanism mediating CEs transfer is still unknown, even the structural features of CETP in a physiological environment remain elusive. We performed molecular dynamics simulations to explore the structural features of CETP in an aqueous solution. Results show that the distal portion flexibility of N-terminal β-barrel domain is considerably greater in solution than in crystal; conversely, the flexibility of helix X is slightly less. During the simulations the distal end of C-terminal β-barrel domain expanded while the hydrophilic surface increasing more than the hydrophobic surface. In addition, a new surface pore was generated in this domain. This surface pore and all cavities in CETP are stable. These results suggest that the formation of a continuous tunnel within CETP by connecting cavities is permitted in solution.