Localized thermal perturbation alters lipid bilayer structure and daunorubicin interactions in MscL-containing membrane systems

Cancer poses one of the major challenges to human mortality; however, conventional chemotherapy is limited by off-target toxicity and non-specific drug distribution. Stimuli-responsive nanocarriers have been explored to address these limitations and enhance targeted therapeutic efficacy. In this study, all-atom molecular dynamics (MD) simulations were employed to investigate the structural and physicochemical response of a mechanosensitive channel of large conductance (MscL)-containing lipid bilayer under localized thermal perturbation. The MscL protein, embedded within a DSPC/DSPG/cholesterol lipid membrane, was subjected to local thermal gradients (ΔT = 10–40 K) to represent localized heating. Structural characterization revealed that localized heating increased the average area per lipid (APL), reduced membrane thickness, decreased the S CD values of lipid tails, and altered the membrane mass density profile. Collectively, these structural changes were accompanied by altered DNR–membrane interactions, including the initial association of DNR molecules with the lipid interface. In contrast, under physiological conditions (310.15 K), DNR molecules predominantly exhibited aggregation behavior near the membrane interface. Furthermore, the simulations showed that at the highest investigated temperature of 350.15 K, significant water permeation and membrane structural perturbations occurred without complete disruption of the overall lipid structure. These findings provide molecular-level insights into the physical behavior of MscL-containing membranes under thermal stress, establishing a baseline for understanding thermoresponsive lipid systems.