Effects of the Size, Shape,and Structural Transition of Thermosensitive Polypeptides on the Stabilityof Lipid Bilayers and Liposomes.

We performed all-atom and coarse-grained (CG) moleculardynamics (MD) simulations of lipid bilayers grafted with elastin-likepolypeptides (ELPs; [VPGVG]n). All-atomsimulations of a single ELP in water show that ELPs become more collapsedand folded as the temperature increases from 293 up to 353 K, in agreementwith experiments. All-atom simulations of lipid bilayers composedof dipalmitoylglycerophosphocholine (DPPC), cholesterol, and fattyacids grafted with ELPs show that ELPs insert into the bilayer andsignificantly disorder lipids, to an extent that depends on the ELPlength over the temperature range 293–323 K. In the bilayer,ELPs are mainly, but not entirely, random coil in character at temperaturesbetween 293 and 315 K and, in contrast to the behavior in water, becomeincreasing random coil and extended in length over the range 315–323K, over which the bilayer is in the disordered liquid phase. The insertionof ELPs into the lipid-tail region is mediated by the interactionof hydrophobic Pro and Val residues with lipid tails, which becomestronger at increased temperature, but the insertion is incompletebecause of the interaction between hydrophilic backbones of Gly residuesand the lipid headgroups. Longer time CG simulations of the transitionfrom ordered gel to disordered liquid bilayer at 315 K in a liposomeare able to capture cholesterol flip-flops between bilayer leaflets,leading to an increase in the number of cholesterols in the innerlayer, which helps the bilayer accommodate the reduced membrane curvatureresulting from the expansion of the bilayer area driven by the phasetransition. Our findings indicate that lipid bilayers can be disruptedmore effectively by the stronger hydrophobic interaction of the randomcoils of ELPs at 315–323 K than by the compact ELPs at 293–310K, which helps explain the experimental observation that ELP-conjugatedliposomes are stable at 310 K, but become unstable and release drugsat 315 K. [ABSTRACT FROM AUTHOR]