Mechanism of Glycans Modulating Cholesteryl Ester Transfer Protein: Unveiled by Molecular Dynamics Simulation

Inhibition
of the cholesteryl ester transfer protein (CETP) has
been considered as a promising way for the treatment of cardiovascular
disease (CVD) for three decades. However, clinical trials of several
CETP inhibitors with various potencies have been marginally successful
at best, raising doubts on the target drugability of CETP. The in-depth
understanding of the glycosylated CETP structure could be beneficial
to more definitive descriptions of the CETP function and the underlying
mechanism. In this work, large-scale molecular dynamics simulations
were performed to thoroughly explore the mechanism of glycans modulating
CETP. Here, the extensive simulation results intensely suggest that
glycan88 tends to assist CETP in forming a continuous tunnel throughout
interacting with the upper-right region of the N-barrel, while it
also could prevent the formation of a continuous tunnel by swinging
toward the right-rear of the N-barrel. Furthermore, glycan240 formed
stable H-bonds with Helix-B and might further stabilize the central
cavity of CETP. Furthermore, the nonspecific involvement of the hydroxyl
groups from the various glycans with protein core interactions and
the similar influence of different glycans trapped at similar regions
on the protein structure suggest that physiological glycan may lead
to a similar effect. This study would provide valuable insights into
devising novel methods for CVD treatment targeting CETP and functional
studies about glycosylation for other systems.