We computationally investigate the critical interactions between an Atomic Force Microscopy (AFM) tip and various lipid nanoconstructs using a multiscale modeling approach. We developed a multiscale computational model by employing coarse-grained MARTINI molecular dynamics simulations to elucidates the complex molecular mechanisms underlying the experimentally observed AFM tip-lipid interaction. Our model comprises different lipid systems, such as 1-palmitoyl-2-oleoyl-glycero-3-phosphocholine (POPC) lipids with glycerol as solvent on a substrate and a mixed POPC and 1,2-dipalmitoylphosphatidylcholine (DPPC) lipid system on a substrate, both interacting with a pyramidal-shaped amorphous silica AFM tip. Our study delves into the intricate forces at play at the lipid membrane surface during penetration, and the energy landscape that governs the mechanically interaction between different constructs during AFM tip indentation. Additionally, we examine the local mechanics, the packing, and the size-dependent mechanics of the system. Ultimately, we establish a structure-force relationship that correlate various experimental force patterns with local lipid packing. The insights derived from this study are anticipated to significantly influence the future design of biomaterials and nanotechnologies in drug delivery and biosensing applications.
