期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 114, 期 47, 页码 E10056-E10065出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1706600114
关键词
self-assembly; coarse-grained molecular dynamics; HIV packaging and budding; Gag; CA-SP1 junction
资金
- European Molecular Biology Laboratory
- State of Illinois
- National Science Foundation [OCI-0725070, ACI-1238993, OCI-1440027]
- Deutsche Forschungsgemeinschaft [BR 3536/2-1]
- Howard Hughes Medical Institute
- National Institute of General Medical Sciences of the National Institutes of Health [P50-GM082545]
- Chica und Heinz Schaller Stiftung
- Medical Research Council [MC_UP_1201/16] Funding Source: researchfish
- Direct For Computer & Info Scie & Enginr
- Office of Advanced Cyberinfrastructure (OAC) [1440027] Funding Source: National Science Foundation
- MRC [MC_UP_1201/16] Funding Source: UKRI
The packaging and budding of Gag polyprotein and viral RNA is a critical step in the HIV-1 life cycle. High-resolution structures of the Gag polyprotein have revealed that the capsid (CA) and spacer peptide 1 (SP1) domains contain important interfaces for Gag self-assembly. However, the molecular details of the multimerization process, especially in the presence of RNA and the cell membrane, have remained unclear. In this work, we investigate the mechanisms that work in concert between the polyproteins, RNA, and membrane to promote immature lattice growth. We develop a coarse-grained (CG) computational model that is derived from sub nano-meter resolution structural data. Our simulations recapitulate contiguous and hexameric lattice assembly driven only by weak anisotropic attractions at the helical CA-SP1 junction. Importantly, analysis from CG and single-particle tracking photo-activated localization (spt-PALM) trajectories indicates that viral RNA and the membrane are critical constituents that actively promote Gag multimerization through scaffolding, while over expression of short competitor RNA can suppress assembly. We also find that the CA amino-terminal domain imparts intrinsic curvature to the Gag lattice. As a consequence, immature lattice growth appears to be coupled to the dynamics of spontaneous membrane deformation. Our findings elucidate a simple network of interactions that regulate the early stages of HIV-1 assembly and budding.
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