TCB Publications - Abstract

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 Ás-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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