[SCAN] Sugar Camouflage: Computational protein Design faces the glycan shield

Title: Sugar Camouflage: Computational protein Design faces the glycan shield

Speaker: Cláudio M. Soares

Abstract: Viruses use diverse mechanisms to attach to and enter host cells, typically through interactions with membrane proteins, glycans, and other host factors. The viral Proteins mediating Host Attachment and Viral Entry (PHAVEs) are therefore key drug targets for both small molecules and biologics.

Most PHAVEs are glycosylated, and their glycans can shield underlying protein surfaces, mimic host motifs, and promote immune evasion. This host–virus arms race directly impacts drug design: glycan shielding reduces accessible epitope area, which is particularly limiting for designing biologics that rely on extended protein-protein interfaces. Reliable characterization of glycan conformations and their structural consequences is thus essential, but experimentally challenging due to glycan heterogeneity (cell type and environment dependence) and high conformational flexibility.

To address this, we performed molecular dynamics (MD) simulations of PHAVEs using representative glycan types. These are multi-microsecond MD simulations of PHAVEs from RSV, Zika, and Nipah viruses, highlighting the need for long timescales, multiple replicates, and rigorous analysis to capture glycan dynamics. The relevance of this approach to drug discovery is illustrated with a case study on RSV, where a set of 13 miniproteins was designed for binding an unshielded region of the F-protein. Six of these exhibit high affinity and potent neutralization.

SCANs are weekly seminars that happen every Wednesday at noon by in-house researchers and invited speakers at ITQB NOVA.