Structural Insight into Inhibition of CsrA-RNA Interaction Revealed by Docking, Molecular Dynamics and Free Energy Calculations

Scientific Reports
Xiaodong RenChangwei Wang

Abstract

The carbon storage regulator A (CsrA) and its homologs play an important role in coordinating the expression of bacterial virulence factors required for successful host infection. In addition, bacterial pathogens with deficiency of CsrA are typically attenuated for virulence. In 2016, the first series of small-molecule inhibitors of CsrA-RNA interaction were identified, which were found to achieve the CsrA-RNA inhibition by binding to the CsrA, without interfering with the RNA. However, the binding mechanism of these inhibitors of CsrA is not known. Herein, we applied molecular docking, molecular dynamics and binding free energy calculations to investigate the binding mode of inhibitors to CsrA. We found that the G11(RNA)-binding site is the most important binding site for CsrA inhibitors. An inhibitor with the proper size range can bind to that site and form a stable complex. We also found that inhibitors with larger size ranges bind to the entire CsrA-RNA interface, but have loose binding. However, this loose binding still resulted in inhibitory activity. The calculated binding free energy from MM/GBSA has a good correlation with the derived experimental binding energy, which might be used as a tool to further select CsrA inh...Continue Reading

References

Mar 6, 1975·Nature·J Shine, L Dalgarno
Dec 8, 1995·The Journal of Biological Chemistry·N A SabnisT Romeo
Oct 24, 2002·Journal of Computational Chemistry·Araz JakalianChristopher I Bayly
Apr 16, 2003·Molecular Microbiology·Thomas WeilbacherTony Romeo
Nov 18, 2003·Molecular Microbiology·Ari B Molofsky, Michele S Swanson
Apr 3, 2004·Nature Reviews. Drug Discovery·Michelle R Arkin, James A Wells
Apr 28, 2004·Drug Discovery Today·Andrew L HopkinsAlexander Alex
Apr 30, 2004·Journal of Computational Chemistry·Junmei WangDavid A Case
May 4, 2005·Journal of Bacteriology·Pablo GutiérrezKalle Gehring
Oct 4, 2005·Journal of Computational Chemistry·David A CaseRobert J Woods
Nov 3, 2005·Molecular Microbiology·Derrick H LenzBonnie L Bassler
Dec 20, 2005·Journal of Molecular Biology·Stephan HeebPaul Williams
Aug 21, 2007·Nature Structural & Molecular Biology·Mario SchubertFrédéric H-T Allain
Apr 29, 2009·Journal of Computational Chemistry·Garrett M MorrisArthur J Olson
May 7, 2010·Cellular and Molecular Life Sciences : CMLS·Johan Timmermans, Laurence Van Melderen
Jan 1, 2007·Journal of Chemical Theory and Computation·John MonganAlexey Onufriev
May 25, 2011·Applied Microbiology and Biotechnology·Elisabeth Sonnleitner, Dieter Haas
Aug 15, 2012·Journal of Cheminformatics·Marcus D HanwellGeoffrey R Hutchison
Aug 28, 2013·Proceedings of the National Academy of Sciences of the United States of America·Jeremiah N MardenMatthew C Wolfgang
Feb 25, 2014·Nucleic Acids Research·Olivier DussFrédéric H-T Allain
May 16, 2014·Nature·Olivier DussFrédéric H-T Allain
Mar 19, 2015·Frontiers in Microbiology·Elke Van AsscheHans P Steenackers
Apr 3, 2015·Microbiology and Molecular Biology Reviews : MMBR·Christopher A VakulskasTony Romeo
Apr 4, 2015·Expert Opinion on Drug Discovery·Samuel Genheden, Ulf Ryde
Apr 16, 2015·Nucleic Acids Research·Sebastian SalentinMichael Schroeder
Jun 10, 2015·Antimicrobial Agents and Chemotherapy·Yasushi ItohKazumasa Ogasawara
Nov 1, 2007·Journal of Chemical Theory and Computation·Jianyin ShaoThomas E Cheatham
Jun 3, 2016·Future Medicinal Chemistry·Christine K MaurerRolf W Hartmann
Aug 24, 2016·Proceedings of the National Academy of Sciences of the United States of America·Florian AltegoerGert Bange

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Citations

May 2, 2018·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Yankun ChenYanling Zhang
Mar 24, 2021·The Journal of Physical Chemistry. B·Agustín OrmazábalGustavo Pierdominici-Sottile
Jan 31, 2018·Journal of Chemical Theory and Computation·Saeed IzadiAlexey V Onufriev

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Methods Mentioned

BETA
X-ray

Software Mentioned

Autodock
Amber16
PMEMD
Amber
cpptraj
Avogadro
GBSA
Pymol
MS Excel
MM

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