Recent experiments in our lab (Phys. Chem. Chem. Phys., 2016, 18, 10129–10137) suggested using leucine zipper peptides to enhance the thermosensitivity of liposomes. To understand the mechanisms of temperature-responsive control by the leucine zipper peptide in liposomes, we firstly performed quantum mechanics calculations and implicit-solvent replica exchange molecular dynamics simulations to study the thermo-stability of two leucine zipper peptides, CH₃(CH₂)₄–CO–[VAQLEVK-VAQLESK-VSKLESK-VSSLESK] (termed the capped peptide) and A-[VAQLEVK-VAQLESK-VSKLESK-VSSLESK] (termed the ALA peptide). The analysis of dihedral angle principal components and protein secondary structures was conducted to determine the temperature-dependence conformation transition of the two peptides. Simulation results revealed that our computed transition temperature of the capped peptide is 319.1 K that accords with experimental measurement, 321.1 K. Later, explicit-solvent conventional molecular dynamics simulations were carried out to examine the process of folding and unfolding of the ALA and capped peptides complexed with a lipid bilayer and water in the vicinity of their transition temperatures. A further analysis of conformation and energy of the folded peptides showed that the increase of temperature gives rise to a notable decrease in the number of intra-chain hydrogen bonds and a significant increase in the potential energy of the peptides, thereby reducing the folding stability of the two peptides. As compared to the ALA peptide, a lower transition temperature caused by less intra-chain hydrogen bonds was observed in the capped peptide, which is closer to the temperature of tumor cells. This fact suggests that the capped peptide is more suitable to produce highly sensitive liposomes for the delivery of cancer drugs.