Abstract
Since spheroidal HDL particles (sHDL) are highly dynamic, molecular dynamics (MD) simulations are useful for obtaining structural models. Here we use MD to simulate sHDL with stoichiometries of reconstituted and circulating particles. The hydrophobic effect during simulations rapidly remodels discoidal HDL containing mixed lipids to sHDL containing a cholesteryl ester/triglyceride (CE/TG) core. We compare the results of simulations of previously characterized reconstituted sHDL particles containing two or three apoA-I created in the absence of phospholipid transfer protein (PLTP) with simulations of circulating human HDL containing two or three apoA-I without apoA-II. We find that circulating sHDL compared with reconstituted sHDL with the same number of apoA-I per particle contain approximately equal volumes of core lipid but significantly less surface lipid monolayers. We conclude that in vitro reconstituted sHDL particles contain kinetically trapped excess phospholipid and are less than ideal models for circulating sHDL particles. In the circulation, phospholipid transfer via PLTP decreases the ratio of phospholipid to apolipoprotein for all sHDL particles. Further, sHDL containing two or three apoA-I adapt to changes in surface area by condensation of common conformational motifs. These results represent an important step toward resolving the complicated issue of the protein and lipid stoichiometry of circulating HDL.
Highlights
Since spheroidal High density lipoproteins (HDLs) particles are highly dynamic, molecular dynamics (MD) simulations are useful for obtaining structural models
Since HDL[1] is beyond the range of their density isolates, the stoichiometry of the S2-18 particle is incorrect; MD simulation produces a particle in which the core lipid is insufficiently covered by the surface protein and lipid
We monitored the structural and dynamic behavior of each model spheroidal HDL particles (sHDL) particle using two different MD methodologies: i) MD-simulated annealing (MDSA) allows the exploration of an increased conformational space via AA simulations and an initial temperature jump; and ii) coarse-grained molecular dynamics (CGMD) allows the exploration of a longer time scale by using CG simulations to decrease computational costs
Summary
Since spheroidal HDL particles (sHDL) are highly dynamic, molecular dynamics (MD) simulations are useful for obtaining structural models. We use MD to simulate sHDL with stoichiometries of reconstituted and circulating particles. We compare the results of simulations of previously characterized reconstituted sHDL particles containing two or three apoA-I created in the absence of phospholipid transfer protein (PLTP) with simulations of circulating human HDL containing two or three apoA-I without apoA-II. We find that circulating sHDL compared with reconstituted sHDL with the same number of apoA-I per particle contain approximately equal volumes of core lipid but significantly less surface lipid monolayers. SHDL containing two or three apoA-I adapt to changes in surface area by condensation of common conformational motifs. These results represent an important step toward resolving the complicated issue of the protein and lipid stoichiometry of circulating HDL.—Segrest, J.
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