Molecular Dynamics Simulated Annealing of Phospholipid- rich HDL

All-atom MD simulations by us of an atomistic double belt model for discoidal HDL produced particles where the apoA-I belt underwent conformational changes coordinated with a distortion of the bilayer disc into a minimal surface patch. Due to short simulations, these particles might represent kinetically trapped intermediates. Here we report all-atom MD simulated annealing as a more robust approach to particle structure. Temperature jumps, in explicit water without constraints, were performed on the published 100:2 particle (molar ratio = POPC:D40apoA-I). While 525K produced rapid vaporization, three 500K simulations for 20ns produced no vaporization. Analyses of average changes in structural parameters during simulation showed: i) SASA of acyl chains rapidly increased 5-fold, then plateaued, a result of expansion of an intact bilayer. ii) Total apoA-I helicity decreased from 95% to 72%. iii) SASA of the lipid-associating hydrophobic residues of apoA-I increased 60%. Using stability at 500K as one measure of helix stability, the figure above shows changes in helicity of individual residues within tandem helical repeats averaged over the three simulations. We conclude that much of apoA-I in PL-rich HDL has no “fixed” conformation, end domains being more labile than central ones.