(608d) Exploring the Effect of Mlkl Protein at the Membrane Interface: A Molecular Dynamics Study

Lipid-protein interactions are currently under study for different disease treatments because they are relevant in several biological functions, such as necroptosis. Necroptosis is a programmed cell death pathway, the last stage in this pathway is the permeabilization of the plasma membrane (PM) by the mixed lineage kinase-like protein (MLKL). Necroptosis is currently under investigation as a potential treatment target for cancer, neurodegenerative, and inflammatory diseases. The molecular mechanism behind membrane permeabilization in necroptosis is still unknown. Here, we provide insights into lipid-protein interaction using long molecular dynamics simulations of a complex model for the PM and the MLKL protein. Our results show that the interaction of MLKL with the membrane is initially driven by the electrostatic interactions of positively charged residues. The protein bound conformation modulates lipid recruitment to the binding site, which changes the local membrane environment generating a unique fingerprint. Phosphoinositol lipids and cholesterol are notably recruited to the protein binding site. Furthermore, Q53 residue was consistently inserted into the membrane where the protein binds horizontally/vertically. Molecular-level understanding of this mechanism will increase our understanding of interaction dynamics at the membrane interface and could enable better design of therapeutics in the context of the necroptosis. Conclusions from this work are applicable to general lipid-protein interactions, particularly in cases of membrane remodeling by peripheral membrane proteins.