Calculating proton uptake/release and binding free energy taking into account ionization and conformation changes induced by protein-inhibitor association: application to plasmepsin, cathepsin D and endothiapepsin-pepstatin complexes

Proteins
Emil Alexov

Abstract

The protein-inhibitor binding energies of enzymes are often pH dependent, and binding induces either proton uptake or proton release. The proton uptake/release and the binding energy for three complexes with available experimental data were numerically studied: pepstatin-cathepsin D, pepstatin-plasmepsin II and pepstatin-endothiapepsin. Very good agreement with the experimental data was achieved when conformational changes were taken into account. The role of the desolvation energy and the conformational changes was revealed by modeling the complex, the separated molecules in the complex conformation and the free molecules. It was shown that the conformational changes induced by the complex formation are as important for the proton transfer as the loss of solvation energy caused by the burial of interface residues. The residues responsible for the proton transfer were identified and their contribution to the proton uptake/release calculated. These residues were found to be scattered along the whole protein rather than being localized only at the active site. In the case of cathepsin D, these residues were found to be highly conserved among the cathepsin D sequences of other species. It was shown that conformation and ionization...Continue Reading

References

Aug 1, 1984·Quarterly Reviews of Biophysics·A Warshel, S T Russell
Aug 20, 1984·FEBS Letters·L Pearl, T Blundell
Sep 22, 1995·Journal of Molecular Biology·J Gómez, E Freire
Mar 1, 1993·Proteins·A S YangB Honig
May 6, 1994·Journal of Molecular Biology·J AntosiewiczM K Gilson
Jul 15, 1993·Proceedings of the National Academy of Sciences of the United States of America·E T BaldwinJ W Erickson
May 20, 1993·Journal of Molecular Biology·A S Yang, B Honig
Jan 9, 1996·Proceedings of the National Academy of Sciences of the United States of America·S Jones, J M Thornton
Sep 17, 1996·Proceedings of the National Academy of Sciences of the United States of America·A M SilvaJ W Erickson
Aug 30, 1996·Biophysical Chemistry·K A Sharp
Sep 1, 1997·Nucleic Acids Research·S F AltschulD J Lipman
Oct 23, 1998·Nature Structural Biology·A Y LeeJ W Erickson
Apr 21, 1999·Protein Science : a Publication of the Protein Society·J TrylskaM K Gilson
Sep 1, 1999·Proceedings of the National Academy of Sciences of the United States of America·E Freire
Sep 2, 1999·Protein Engineering·J E NielsenR C Wade
Sep 29, 1999·Proceedings of the National Academy of Sciences of the United States of America·J J Havranek, P B Harbury
Apr 8, 2000·Current Opinion in Structural Biology·F B SheinermanB Honig
Mar 27, 2001·Protein Science : a Publication of the Protein Society·L P Lee, B Tidor
Jan 24, 2002·Molecular Cell·Diana Murray, Barry Honig
Jun 11, 2002·Journal of Molecular Biology·Felix B Sheinerman, Barry Honig
Jul 12, 2002·Proteins·William R ForsythAndrew D Robertson
Sep 27, 2002·Biophysical Journal·Roxana E GeorgescuMarilyn R Gunner
Jan 23, 2003·Protein Science : a Publication of the Protein Society·Jens Erik Nielsen, J Andrew McCammon
Mar 5, 2003·Journal of Molecular Biology·Oluwatoyin A AsojoAbelardo M Silva

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Citations

Jul 31, 2013·Quarterly Reviews of Biophysics·Alexey V Onufriev, Emil Alexov
May 17, 2011·Physical Biology·Zhe ZhangEmil Alexov
Jan 1, 2008·PMC Biophysics·Kemper TalleyEmil Alexov
Mar 24, 2011·Future Medicinal Chemistry·Predrag Kukić, Jens Erik Nielsen
Sep 14, 2011·The Journal of Physical Chemistry. B·Ting ShiJian Zhang
Jul 24, 2015·Biopolymers·M Olivia Kim, J Andrew McCammon
Feb 3, 2011·Proteins·Rooplekha C MitraEmil Alexov
Jul 12, 2011·Proteins·Tim MeyerErnst-Walter Knapp
Jul 4, 2006·Journal of Molecular Graphics & Modelling·Jens Erik Nielsen
May 20, 2015·Frontiers in Molecular Biosciences·Lin LiEmil Alexov
Jun 22, 2017·Proceedings of the National Academy of Sciences of the United States of America·Amit Kumawat, Suman Chakrabarty
Jul 7, 2015·PLoS Computational Biology·Marharyta PetukhEmil Alexov
Feb 8, 2007·European Biophysics Journal : EBJ·A IsvoranE Alexov
Jan 10, 2020·Journal of Biomolecular Structure & Dynamics·Shuaizhen TianJohn Z H Zhang
Apr 11, 2020·International Journal of Molecular Sciences·Swagata PahariEmil Alexov
Oct 28, 2008·The Journal of Physical Chemistry. B·Zofia Piłat, Jan M Antosiewicz
Feb 24, 2006·The Journal of Physical Chemistry. B·Maja Mihajlovic, Themis Lazaridis
Sep 21, 2017·The Journal of Physical Chemistry Letters·Robert C HarrisJana Shen
Jul 12, 2011·Journal of Chemical Theory and Computation·Chresten R SøndergaardJan H Jensen
Oct 13, 2020·The Journal of Physical Chemistry Letters·Amit Kumawat, Suman Chakrabarty
Dec 30, 2021·Journal of Chemical Information and Modeling·Jack A Henderson, Jana Shen

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