From Discoidal to Spheroidal HDL particles through Coarse Grained and All Atom Molecular Dynamics Simulations

In vivo high density lipoproteins (HDL) originate as discoidal complexes of apolipoprotein (apo) A-I, phospholipids (PL) and cholesterol. These nascent HDL complexes are remodeled by the enzyme Lecithin Cholesterol Acyl Transferase (LCAT), that catalyses the transition from discoidal (PL-rich) to spherical HDL (the form of circulating HDL) by generating cholesteryl esters (CE) and lyso-PC. The phase separation of neutral lipids, CE and triglycerides (TG), creates a hydrophobic core encapsulated by the protein and amphipathic lipid molecules. To investigate the conformational change of apoA-I in the transition from PL-rich to CE-rich HDL particles, we initially performed all atom (AA) and coarse grained (CG) molecular dynamics (MD) simulations at 310 K on two starting model discoidal HDL particles containing palmitoyloleoylphosphatidylcholine (POPC), cholesterol (UC) and full length apoA-I molecules with molar ratios of 160:24:2 and 160:64:2, respectively. In the 100 ns coarse grained structures a fraction of the cholesterol molecules was mutated to cholesteryl oleate (CO) molecules and an equivalent number of POPC molecules were removed. The main goal was to mimic the LCAT activity in silico by simulating model CE-rich HDL particles representing small HDL2 particles with a cholesterol concentration similar to that of circulating HDL. Then, the two mutated structures containing POPC:CO:UC:apoA-I molar ratios of 142:18:6:2 and 105:55:9:2, respectively, were subjected to a 100 ns CG MD simulation at 310K. In both CG MD simulations CO molecules form a hydrophobic core in the 100 ns time scale, indicating that hydrophobic interactions play an active role in the stabilization of spheroidal HDL particles. It is also interesting to note the separation of UC molecules, as observed experimentally, into two distinct environments: free and bound to the protein. This work was supported by the National Institute of Health