Boon Chong Goh, Juan R. Perilla, Matthew R. England, Katrina J. Heyrana,
Rebecca C. Craven, and Klaus Schulten.
Atomic modeling of an immature retroviral lattice using molecular
dynamics and mutagenesis.
Structure, 23:1414-1425, 2015.
(PMC: PMC4526393)
GOH2015
Defining the molecular interaction between Gag proteins in a fully assembled
hexagonal lattice of
immature retrovirus particles is crucial for elucidating the mechanisms of virus assembly
and maturation, as well as for identifying new drug targets. Recent advances in cryo-
electron microscopy
(cryo-EM) have yielded subnanometer structural information on the morphology of
immature Gag
lattices of two retroviruses, namely Mason-Pfizer monkey virus (M-PMV) and
human immunodeficiency virus type 1 (HIV-1), making computational modeling and
simulations
feasible for investigating the Gag-Gag interactions at the atomic level. We have examined
the structure of the
alpharetrovirus, Rous sarcoma virus (RSV) using homology modeling, all-atom molecular
dynamics simulations and in vitro assembly, to create the first all-atom model of
an immature retroviral
lattice. In particular, a 9 µs-long replica exchange molecular dynamics simulation of the
spacer
peptide (SP)-nucleocapsid (NC) subdomains results in a 6-helix bundle with inter-helical
hydrophobic contacts, stabilized by electrostatic interactions involving residues in the
beginning of the NC
domain. The resulting model of the Gag lattice shows features of the packing and
dynamics of the
capsid protein (CA) with implications for the maturation process, and confirms the
stabilizing role
of the upstream and downstream regions of Gag, namely p10 and SP-NC.
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