HIV-1 protease flaps spontaneously close to the correct structure in simulations following manual placement of an inhibitor into the open state

Journal of the American Chemical Society
Viktor HornakCarlos Simmerling

Abstract

We report unrestrained, all-atom molecular dynamics simulations of HIV-1 protease (HIV-PR) with a continuum solvent model that reproducibly sample closing of the active site flaps following manual placement of a cyclic urea inhibitor into the substrate binding site of the open protease. The open form was obtained from the unbound, semi-open HIV-PR crystal structure, which we recently reported (Hornak, V.; et al. Proc. Natl. Acad. Sci. U.S.A. 2006, 103, 915-920.) to have spontaneously opened during unrestrained dynamics. In those simulations, the transiently open flaps always returned to the semi-open form that is observed in all crystal structures of the free protease. Here, we show that manual docking of the inhibitor reproducibly induces spontaneous conversion to the closed form as seen in all inhibitor-bound HIV-PR crystal structures. These simulations reproduced not only the greater degree of flap closure, but also the striking difference in flap "handedness" between bound and free enzyme. In most of the simulations, the final structures were highly accurate. Root-mean-square deviations (RMSD) from the crystal structure of the complex were approximately 1.5 A (averaged over the last 100 ps) for the inhibitor and each flap d...Continue Reading

References

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Jan 19, 2006·Proceedings of the National Academy of Sciences of the United States of America·Viktor HornakCarlos Simmerling

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Citations

May 17, 2012·Journal of Chemical Information and Modeling·Georgios LeonisManthos G Papadopoulos
Oct 13, 2006·Journal of the American Chemical Society·Melinda LaytenCarlos Simmerling
May 13, 2011·Journal of the American Chemical Society·Nan-jie DengRonald M Levy
Jan 17, 2009·The Journal of Physical Chemistry. B·Yuqing Deng, Benoît Roux
Nov 28, 2012·Proceedings of the National Academy of Sciences of the United States of America·S Kashif SadiqGianni De Fabritiis
Sep 13, 2013·Journal of Biomedical Science·Mohammad Reza Dayer, Mohammad Saaid Dayer
Jul 12, 2011·BMC Structural Biology·Yi Mao
Jul 11, 2013·PloS One·Gordon Lemmon, Jens Meiler
Jun 11, 2009·The Journal of Chemical Physics·Dechang LiYonggang Huang
Dec 21, 2010·Journal of Molecular Graphics & Modelling·Yi ShangCarlos Simmerling
Nov 21, 2007·Current Opinion in Structural Biology·Ivet BaharDror Tobi
Feb 6, 2007·Drug Discovery Today·Viktor Hornak, Carlos Simmerling
Sep 27, 2007·Proteins·Rieko Ishima, John M Louis
Aug 18, 2010·Proteins·S Kashif Sadiq, Gianni De Fabritiis
Nov 21, 2007·Biophysical Journal·Leyla CelikEmad Tajkhorshid
Apr 1, 2008·Biophysical Journal·Gennady VerkhivkerRicardo A Broglia
Apr 2, 2015·European Journal of Medicinal Chemistry·Nirnoy Dan, Soumendranath Bhakat
Mar 27, 2013·Journal of Biomolecular Structure & Dynamics·Natércia F BrásMaria J Ramos
Feb 14, 2016·Chemical Biology & Drug Design·Mukul MahantiPär Söderhjelm
Dec 10, 2016·Journal of the American Chemical Society·Agnieszka KrzemińskaKatarzyna Świderek
May 10, 2017·Nature Chemical Biology·Jooyoung ParkNiraj H Tolia
Jan 30, 2015·Molecular BioSystems·Wilson KarubiuMahmoud E S Soliman
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Apr 3, 2008·Biopolymers·Kelly L DammHeather A Carlson
Jul 22, 2014·Journal of Molecular Recognition : JMR·Yu-ming M HuangChia-en A Chang
Oct 3, 2006·The Journal of Biological Chemistry·Salma RafiPeter J Tonge
Apr 21, 2018·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Kaori AsamitsuTakashi Okamoto

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