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J Mol Graph Model. 2017 Jan;71:218-226. doi: 10.1016/j.jmgm.2016.12.003. Epub 2016 Dec 5.

Modeling global changes induced by local perturbations to the HIV-1 capsid.

Author information

1
Department of Computational and Systems Biology, University of Pittsburgh, Suite 3064 Biomedical Science Tower 3, 3501 Fifth Avenue, Pittsburgh, PA 15260, USA. Electronic address: shb2037@med.cornell.edu.
2
Department of Computational and Systems Biology, University of Pittsburgh, Suite 3064 Biomedical Science Tower 3, 3501 Fifth Avenue, Pittsburgh, PA 15260, USA; University of Pittsburgh Drug Discovery Institute, University of Pittsburgh, W965 Biomedical Science Tower, 200 Lothrop Street, Pittsburgh, PA 15261, USA. Electronic address: lezon@pitt.edu.

Abstract

The HIV-1 capsid is a conical protein shell made up of hexamers and pentamers of the capsid protein. The capsid houses the viral genome and replication machinery, and its opening, or uncoating, within the host cell marks a critical step in the HIV-1 lifecycle. Binding of host factors such as TRIM5α and cyclophilin A (CypA) can alter the capsid's stability, accelerating or delaying the onset of uncoating and disrupting infectivity. We employ coarse-grained computational modeling to investigate the effects of point mutations and host factor binding on HIV-1 capsid stability. We find that the largest fluctuations occur in the low-curvature regions of the capsid, and that its structural dynamics are affected by perturbations at the inter-hexamer interfaces and near the CypA binding loop, suggesting roles for these features in capsid stability. Our models show that linking capsid proteins across hexamers attenuates vibration in the low-curvature regions of the capsid, but that linking within hexamers does not. These results indicate a possible mechanism through which CypA binding alters capsid stability and highlight the utility of coarse-grained network modeling for understanding capsid mechanics.

KEYWORDS:

Coarse-grained; Cyclophilin A; Network model; Normal mode analysis; Structural dynamics

PMID:
27951510
DOI:
10.1016/j.jmgm.2016.12.003
[Indexed for MEDLINE]
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