The dense arrangement of N-glycans masking antigenic surfaces on the HIV-1 envelope (Env) protein acts as a shield from the adaptive immune system. The molecular complexity of glycan modifications and their inherent dynamic heterogeneity on a protein surface make experimental studies of glycoprotein structures a challenge. Here we have integrated a high-throughput atomistic modeling with graph-theory based method to capture the native glycan shield topological network and identify concerted behavior of these glycans. This is the first time that a complete computational model of an HIV-1 Env trimeric SOSIP structure has been generated with a native glycosylation pattern including both oligomannose and complex glycans, thus obtaining results which are immunologically more relevant. Important global and local feature differences due to the native-like glycosylation pattern have been identified, that stem from the charged sialic acid tips, fucose rings at the base, and different branching patterns of the complex glycans. Analyses of network attributes have aided in detailed description of the shield in a biological context. We have also derived a measure to quantify the shielding effect based on the number of glycan heavy atoms encountered over the antigenic protein surface that can define regions of relative vulnerability and resilience on the shield, and can be harnessed for potential immunogen design.

A Network-based approach for Quantifying the Resilience and Vulnerability of HIV-1 Native Glycan Shield