Protein glycosylation plays a crucial role in viral pathogenesis, as suggested by the extensive N-glycosylation coat on viral fusion proteins. Recent structural and glycoanalytic studies have shown that the SARS-CoV-2 spike (S) protein is not shielded as effectively as the envelope glycoproteins of “evasion strong” viruses, with the receptor binding domain (RBD) exposed to potential antibody recognition. Also, experimental evidence indicates important differences in the type of glycosylation, where complex, rather than oligomannose N-glycans, constitute the majority of the SARS-CoV-2 S shield1. Understanding the specific functions of this unique glycosylation pattern is particularly tricky because of the glycans' intrinsic conformational disorder prevents them from being easily characterised with standard structural biology techniques. In this talk I will present how high-performance computing (HPC) molecular simulations have contributed to advance our knowledge on the role of glycosylation in the SARS-CoV-2 infection mechanisms2,3. I will focus in particular on how we identified a unique functional role of the glycan shield in the activation of the S glycoprotein2, and on how specific changes in the nature and topology of the glycan shield affect S activity, fine-tuning the S3. In particular, I will discuss how changes in the glycan shield topology are intertwined with the S evolution, and may have increased SARS-CoV-2 infectivity along the phylogenetic tree3, by enhancing ACE2 binding and host cell surface localization through the interaction with glycans expressed on the host cell surface and extracellular matrix4.