Autophagy and evasion of immune system by SARS-CoV-2. Structural features of the Non-structural protein 6 from Wild Type and Omicron viral strains interacting with a model lipid bilayer. ^†

The viral cycle of SARS-CoV-2 is based on a complex interplay with the cellular machinery, which is mediated by specific proteins eluding or hijacking the cellular defense mechanisms. Among the complex pathways called by the viral infection autophagy is particularly crucial and is strongly influenced by the action of the non-structural protein 6 (Nsp6) interacting with the endoplasmic reticulum membrane. Importantly, differently from other non-structural proteins Nsp6 is mutated in the recently emerged Omicron variant, suggesting a possible different role of autophagy. In this contribution we explore, for the first time, the structural property of Nsp6 thanks to long-time scale molecular dynamic simulations and machine learning analysis, identifying the interaction patterns with the lipid membrane. We also show how the mutation brought by the Omicron variant may indeed modify some of the specific interactions, and more particularly help anchoring the viral protein to the lipid bilayer interface.