Lipid nanobubbles as nanoscale materials that combine the biocompatibility of lipids, the physicochemical properties of nanobubbles, and the therapeutic potential of gas molecules, exhibit broad application prospects in fields such as ultrasound molecular imaging, gene/drug delivery, and gas therapy. To further achieve the precise application of these lipid nanobubbles, it is essential to gain a deeper understanding of their interaction mechanisms with biological systems. Molecular dynamics (MD) simulation provides a powerful computational tool for this purpose. However, previous simulations of nanobubble/lipid nanobubbles typically used vacuum as the gas core, which is not suitable for studying the interactions between functional lipid nanobubbles with biological systems, especially the biological applications of gas molecules. Therefore, in our work, based on the CGenFF and ffTK tools, we have developed and optimized the CHARMM36 all-atom force field parameters for six gas molecules including N₂, O₂, H₂, CO, CO₂, and SO₂. These parameters accurately reproduce the gas density under various pressures，the spontaneous formation of gas nanobubbles, as well as the self-assembly process of lipid nanobubbles. Additionally, we have developed a Python script (AA-LNB.py) for generating all-atom lipid nanobubble simulation systems, and have confirmed its effectiveness in all-atom MD simulations. It is capable of accurately capturing the dynamic behavior of gas molecules at the gas-lipid and lipid-water interfaces. In summary, our proposed all atomic gas model is suitable for simulating free gas nanobubbles and lipid nanobubbles, overcoming the limitations of previous simulation methods that used vacuum as the gas core and were limited to isothermal-isochoric (NVT) ensemble, which will be important for revealing the molecular-level interactions between lipid nanobubbles and biological systems.

Xubo Lin

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