The free energy landscape of retroviral integration

Willem Vanderlinden (), Tine Brouns, Philipp U. Walker, Pauline J. Kolbeck, Lukas F. Milles, Wolfgang Ott, Philipp C. Nickels, Zeger Debyser and Jan Lipfert ()
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Willem Vanderlinden: Nanosystems Initiative Munich, Center for NanoScience, LMU Munich
Tine Brouns: KU Leuven, Division of Molecular Imaging and Photonics
Philipp U. Walker: Nanosystems Initiative Munich, Center for NanoScience, LMU Munich
Pauline J. Kolbeck: Nanosystems Initiative Munich, Center for NanoScience, LMU Munich
Lukas F. Milles: Nanosystems Initiative Munich, Center for NanoScience, LMU Munich
Wolfgang Ott: Nanosystems Initiative Munich, Center for NanoScience, LMU Munich
Philipp C. Nickels: Nanosystems Initiative Munich, Center for NanoScience, LMU Munich
Zeger Debyser: KU Leuven, Department of Pharmaceutical and Pharmacological Sciences
Jan Lipfert: Nanosystems Initiative Munich, Center for NanoScience, LMU Munich

Nature Communications, 2019, vol. 10, issue 1, 1-11

Abstract: Abstract Retroviral integration, the process of covalently inserting viral DNA into the host genome, is a point of no return in the replication cycle. Yet, strand transfer is intrinsically iso-energetic and it is not clear how efficient integration can be achieved. Here we investigate the dynamics of strand transfer and demonstrate that consecutive nucleoprotein intermediates interacting with a supercoiled target are increasingly stable, resulting in a net forward rate. Multivalent target interactions at discrete auxiliary interfaces render target capture irreversible, while allowing dynamic site selection. Active site binding is transient but rapidly results in strand transfer, which in turn rearranges and stabilizes the intasome in an allosteric manner. We find the resulting strand transfer complex to be mechanically stable and extremely long-lived, suggesting that a resolving agent is required in vivo.

Date: 2019
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DOI: 10.1038/s41467-019-12649-w

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