The Collective Behavior and Conserved Microdomains of the HIV-1 Envelope Trimer Glycan Shield

Abstract:

The trimeric HIV-1-envelope (Env) spike is one of the most glycosylated protein complexes known, with roughly half its mass comprising host-derived N-linked glycan. Here we use molecular dynamics to provide insight into its structural dynamics and into how both protomer and glycan movements coordinate to shield the Env-protein surface.
A 2-μs molecular dynamics simulation of a fully glycosylated atomistic model of the HIV-1-Env trimer revealed a spectrum of protomer-scissoring and trimer-opening movements.
Network analysis showed highly conserved glycans to combine with protomer scissoring to restrict access to the binding site of the CD4 receptor. The network property of betweenness centrality appeared to identify whether glycans spread to restricted access or clustered to maintain the high-mannose character of the shield. We also observed stable microdomains comprising patches of glycan, with neutralizing antibodies often binding at the interface between glycan microdomains. Overall, our results afford a microsecond-based understanding of the Env-glycan shield.

Biography:

Thomas Lemmin is a postdoctoral researcher in the DeGrado Lab at the University of California, San Francisco (UCSF). His research principally focuses on combining molecular modeling and simulations with available experimental input in order to advance the understanding of mechanisms of complex biological systems and processes on a molecular scale.
He carried out his PhD Thesis work (“ Molecular Modeling of Membrane Embedded Proteins”) under the supervision of Professor Matteo Dal Peraro at the Laboratory for Biomolecular Modeling, Ecole Polytechnique Fédérale de Lausanne (EPFL) . With the support of the Swiss National Science Foundation (SNSF) Postdoctoral Mobility fellowship, he integrated into the DeGrado Lab, where he investigated the molecular determinants of amyloid aggregation linked to Alzheimer’s disease. He also took part in the first example of designed proteins that were able to bind to the unstable form of a small-molecule cofactor. In collaboration with the Vaccine Research Center at the National Institutes of Health (VRC-NIH), he pioneered the use of molecular dynamics simulations and graph theory to investigate the dynamics of the HIV-1 Env glycan shield.