Molecular Interactions of the Matrix Domain of HIV-1 Gag Protein at the Membrane Interface

Abstract

Binding and aggregation of the HIV-1 Gag protein on the plasma membrane (PM) enable budding and release of immature virons, which propagate the viral infection once they reach maturity. The matrix (MA) domain of the Gag protein is responsible for Gag-membrane interactions 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. The binding mechanism and energetics of interaction between MA and the inner leaflet of the PM are still uncertain. NMR studies suggest MA trimerization facilitates Myr exposure from its sequestered conformation inside the hydrophobic pocket of the MA domain, leading to Myr anchoring. Interactions between the HBR of MA and acidic lipids could also play key roles to enable Myr exposure, suggesting the need of lipid domains for MA, therefore Gag, binding. We examined MA-membrane interactions with model membranes using enhanced sampling simulation techniques to gain basic understanding of its binding mechanism. We looked at the effect of lipid composition, specifically the presence of PIP2, on MA binding events as well as the role of Myr in this process. Metadynamics were used to understand the conformational changes that occur during Myr exposure and MA trimerization that stabilize protein binding.