Understanding the Role of RNA in Driving the Clustering of HIV Gag Molecules using Coarse-Grained Molecular Dynamics Models

Abstract

Multi-domain Gag protein is the fundamental building block of the retrovirus particles. In the process of the HIV-1 particle assembly, Gag poly-protein interacts with lipids, with ribonucleic acids (RNAs) and with other Gag proteins. These diverse interactions drive the construction of the infectious particle and the packaging of the viral RNA into the particle. In this work, we have used coarse-grained (CG) molecular dynamics models of plasma membrane, RNA and Gag poly-protein to understand the role of various components in the formation of virus-like particles (VLPs). In particular, we focus on the possible role that the genomic RNA plays as a scaffolding agent in driving the clustering and assembly of Gag proteins on the membrane. We use available CG models of Gag proteins [Ayton & Voth, BJ 2010] and lipids [Srivastava & Voth, JCTC 2012] and develop a new CG model (one-site per nucleotide) for the full genomic RNA using the experimentally available architecture and secondary structure of the entire HIV-1 NL4-3 genome. [Watts et. Al, Nature 2009; Jonikas et al, RNA 2009] Our simulations confirm that the extended Gag molecules are stable only when they are simultaneously associated with both the membrane and the RNA. Using our model, we also show the aggregation of distributed Gag molecules on the membrane surface in presence of RNA strands. Preliminary data from our simulations indicate that existing membrane-bound RNA-Gag seed complexes act as nucleation sites and possibly assist in capturing the diffusing Gag molecule at a distance on the bilayer, slowly increasing the cluster sizes. Large-scale simulation with full genomic RNA is expected to provide further insights into the scaffolding mechanism.