Figure 1.
Structure of CETP and starting configurations for simulations.
A) X-ray structure of CETP from the side (left) and bottom (right). Two DOPCs (grey and blue spheres) plug the tunnel openings that lead to the hydrophobic tunnel where two CETP-bound CEs (orange spheres) are located. Helix X is labelled and marked with a red sphere. B) The starting configuration for droplet simulations. C) The starting configuration for lipid trilayer simulation. POPCs and DOPCs are coloured as grey, CEs are orange, head group nitrogens are blue, and Trp residues green. Water molecules were removed from the snapshots for clarity.
Figure 2.
The binding of CETP to lipid surfaces with different curvatures.
A) Snapshots from the end of atomistic simulations A3 and A4. POPCs are transparent and grey, and COs are orange. Water molecules were omitted for clarity. CETP is rendered using secondary structures and Trp residues are marked with green color. Dashed and yellow lines present the curvature of CETP. B) RMSD and radii of gyration profiles for CETP in droplet and trilayer simulations. C) Radial distribution functions and density profiles for the droplet and trilayer systems, respectively.
Figure 3.
Electrostatic interactions between CETP and lipid droplet.
A) Number of salt bridges formed between the charged residues of CETP and the head groups of POPCs as a function of time. The upper profile shows the number of contacts between the positively charged residues and P atoms of POPCs, and the lower profile shows the number of contacts between the negatively charged amino acids and N atoms of POPCs. B) Salt bridge-forming positively (red) and negatively (blue) charged amino acids marked to the structure of CETP. Trp residues are labeled and green.
Figure 4.
Interaction of CETP with core lipids.
A) Snapshots from the coarse-grained simulations CG3 (left) and CG3-90POPC (right). The upper snapshots show side views and the lower ones top views of CETP bound to a lipid droplet. In the latter, the hydrophobic patch under CETP is clearly visible. The structure of CETP has been rendered using secondary structure information in upper snapshots (β-sheets are yellow, α-helixes violet and random coils gray) or as dark transparent phantom in lower snapshots. The green spheres are Trp residues. POPCs are transparent in the upper snapshots, while those in the bottom snapshots are visible as grey (the choline head groups are visible as blue). CEs are rendered with orange spheres. Water molecules were omitted for clarity. B) Number of contacts between core CEs and CETP with different surface-core lipid ratios as a function of time.
Figure 5.
A) Root mean square fluctuations for atomistic droplet simulations. Loop regions are marked with omegas and the hinge region of helix X has been slightly darkened. B) Residual B-factors mapped to the backbone structure of CETP. Red color indicates the most rigid structures, whereas white and blue indicate the most flexible structural regions. The hinge region of helix X is marked with a transparent blue sphere.
Figure 6.
Hypothesis for the initial event of helix X assisted core lipid exchange.
A) Two RMSD-fitted snapshots from the simulation A3-90POPC showing the rearrangement of helix X (darkened colour). The green conformation is for the open state and the blue one for the closed state. A more detailed structure of helix X and the role of the hinge region during the conformational change (red and transparent region) are shown in the lower snapshots. CEs are shown as orange sticks. The residues 462–476 and 193–202 of CETP have been rendered using sticks, and coloring is based on the polarity of residues. B) Spatial number density of POPCs (grey and transparent) and CEs (orange) during the simulation A3-90POPC. Core CEs diffuse into the hydrophobic tunnel of CETP (green spheres) without helix X. C) Number of contacts between core CEs and interior CE-473 when helix X is in the open state (black) or completely removed (red).