Computational design of binder as the LC3-p62 protein-protein interaction.

Cellular autophagy is an intracellular degradation pathway, which transports damaged, deformed, senescent or non-functional proteins and organelles to lysosome for digestion and degradation. Cellular autophagy is deeply evolutionarily conservedfromyeasttomammaliancells, and many homologous proteins of the autophahgy regulators are found in several species. This physiological process maintains the steady state of cells. Furtheremore, autophagy dysfunction is closely related to various diseases, such as neurodegenerative diseases, inflammation-related diseases, cardiovascular diseases, metabolic diseases, etc. The LC3 and p62 protein protein interaction (PPI) promotes the formation of autophagosomes and delivers polyubiquitinated "cargoes" to autophagic degradation. Therefore, LC3-p62 PPI plays an integral role in the formation of autophagosomes and effectively inhibits autophagy. However, there are still few studies on the LC3-p62 PPI inhibitors for its unclear molecular mechanism. Furthermore, most of these inhibitors are macromolecules with poorly active, and small molecules are particularly scarce. In this article, the computation method was used to identify the hot spot and design peptides as the binder of LC3-p62 PPI. Findings from this work provide a reference for the follow-up research of discovering small molecule inhibitors targeting LC3-p62 PPI.