Glycolipids from pathogenic Mycobacterium tuberculosis play important roles during the interaction of the pathogen with macrophages and can shape the host cell's immune response by modulating its membrane structure and function. Here, we study the phenolic glycolipids (PGLs) present in the envelope of some hypervirulent strains of Mycobacterium tuberculosis and their impact on model membranes. By a combination of molecular modeling and simulations, and solid-state NMR experiments, we show that PGLs, such as the structurally related lipid phthiocerol dimycocerosate, adopt a conical shape in lipid membranes, which destabilizes the lamellar membrane phase and promotes a transition to a nonlamellar inverted-hexagonal phase. Unlike phthiocerol dimycocerosate, in our simulations, PGL remains anchored to the phosphate groups of the lipid bilayer by its sugar-carrying extremity, preventing lipid flip-flop. These findings shed new light on a potential biophysical role of PGLs through modulation of the properties of the host cell's membrane, in addition to the recognition of its sugar moiety by host cell immune receptors.

ADAM10 is a crucial membrane-bound metalloprotease that regulates cellular physiology by cleaving and releasing membrane-anchored proteins, including adhesion molecules and growth factor precursors, thereby modulating cell signaling, adhesion, and migration. Despite its central role, its activation mechanisms are not fully understood. Here, we model how phosphatidylserine (PS) exposure during apoptosis triggers ADAM10 activation. We confirm that PS externalization is associated with ADAM10-mediated CD43 shedding from the surface of T cells. Intriguingly, ADAM10 activation correlated with loss of ADAM10 monoclonal antibody binding, suggesting a PS-induced conformational change that alters epitope accessibility. To explore this lipid-mediated conformational change of ADAM10, we employed molecular dynamics simulations to map its conformational landscape. Our simulations revealed that in the absence of PS, ADAM10 samples predominantly closed and intermediate states. By contrast, the presence of PS destabilizes the closed conformation, thereby favoring open states. We provide a mechanistic explanation for this PS-induced conformational change, which drives ADAM10 activation and loss of mAb binding through conformational change. These findings offer new insights into the lipid-mediated regulation of ADAM10 and its conformational dynamics.