(469j) Computational Modeling of Protein Interactions of the Matrix Domain of HIV-1 Gag

Human immunodeficiency virus type 1 (HIV-1) is the virus that causes AIDS; nearly 2 million people became infected only in 2016, but only a fraction were able to access anti-retroviral therapy by 2017. We need better understanding of the underlying molecular mechanisms that facilitate viral propagation to inspire new and more accessible drug therapies. HIV-1 requires assembly and budding of an immature viral envelope from the plasma membrane (PM) of an infected host to propagate the infection. For this to occur, the Gag polyprotein of HIV-1 must assemble at the inner leaflet of the PM. The matrix (MA) domain of Gag is responsible for membrane targeting through the myristate group (Myr), a fatty acid covalently attached to the N-terminus of the protein, and a highly basic region (HBR) of residues located close to the Myr. It has been previously proposed that MA trimerization enables Myr exposure from the protein cavity and facilitates membrane binding. Using molecular dynamics (MD) simulations, we explored the binding mechanism and energetics of MA to model membranes and to other MA units.

We simulated the MA domain in solvent as well as in the vicinity of membrane models to characterize different interacting conformations. The membrane models account for different key aspects of the inner leaflet of the PM, such as charge, sterol content, or the ability to form lipid domains to determine the influence of membrane structure on protein binding. Additionally, we computed membrane properties with and without the protein to determine the membrane response to protein binding. Enhanced sampling techniques were used to examine the mechanism of Myr insertion into a bilayer as well as the energetics of MA trimerization. The all-atom simulations provide insights on key protein-protein and protein-lipid interactions that promote and stabilize PM targeting. The data collected from these studies was used to develop a coarse-grained model for MA, which will allow us to study its binding cooperativity and further characterize the lateral organization of the protein at the membrane surface.

This work serves to advance our understanding of key mechanisms in the viral replication of HIV-1 and offers new perspectives for inhibitor-based antiretroviral treatments. Additionally, it provides insight into the general dynamics of peripheral proteins at the membrane interface and relevant protein-membrane interactions of lipidated proteins that are common across several viruses.