Calculated pKa Variations Expose Dynamic Allosteric Communication Networks

Journal of the American Chemical Society
Eric J M LangEmily J Parker

Abstract

Allosteric regulation of protein function, the process by which binding of an effector molecule provokes a functional response from a distal site, is critical for metabolic pathways. Yet, the way the allosteric signal is communicated remains elusive, especially in dynamic, entropically driven regulation mechanisms for which no major conformational changes are observed. To identify these dynamic allosteric communication networks, we have developed an approach that monitors the pKa variations of ionizable residues over the course of molecular dynamics simulations performed in the presence and absence of an allosteric regulator. As the pKa of ionizable residues depends on their environment, it represents a simple metric to monitor changes in several complex factors induced by binding an allosteric effector. These factors include Coulombic interactions, hydrogen bonding, and solvation, as well as backbone motions and side chain fluctuations. The predictions that can be made with this method concerning the roles of ionizable residues for allosteric communication can then be easily tested experimentally by changing the working pH of the protein or performing single point mutations. To demonstrate the method's validity, we have applie...Continue Reading

References

Jan 1, 1984·European Biophysics Journal : EBJ·A Cooper, D T Dryden
Dec 5, 1993·Journal of Molecular Biology·A Sali, T L Blundell
Feb 1, 1996·Journal of Molecular Graphics·W HumphreyK Schulten
Apr 11, 1997·Journal of Molecular Biology·H X Zhou, M Vijayakumar
Dec 17, 2002·Nature Structural Biology·Gürol M SüelRama Ranganathan
Jan 24, 2003·Proceedings of the National Academy of Sciences of the United States of America·Markus HartmannGerhard H Braus
May 1, 1965·Journal of Molecular Biology·J MONODJ P CHANGEUX
Dec 17, 2003·Current Opinion in Structural Biology·Dorothee Kern, Erik R P Zuiderweg
Jul 29, 2004·Proteins·Michael S LeeCharles L Brooks
May 1, 1997·Acta Crystallographica. Section D, Biological Crystallography·G N MurshudovE J Dodson
Oct 14, 2005·Journal of Computational Chemistry·James C PhillipsKlaus Schulten
Dec 16, 2005·Proteins·Oliver F Lange, Helmut Grubmüller
Dec 22, 2005·Acta Crystallographica. Section D, Biological Crystallography·Philip Evans
Jul 18, 2006·Nucleic Acids Research·Barbara M Tynan-Connolly, Jens Erik Nielsen
Aug 19, 2006·Journal of Computational Chemistry·Nicholas M Glykos
Apr 22, 1997·Biophysical Chemistry·L Sandberg, O Edholm
Jun 19, 2008·Protein Science : a Publication of the Protein Society·Qiang Cui, Martin Karplus
Jul 22, 2008·Nature Chemical Biology·Nina M Goodey, Stephen J Benkovic
Jan 24, 2009·The Journal of Biological Chemistry·C Nick PaceJ Martin Scholtz
Mar 11, 2009·Journal of Computational Chemistry·Yifan SongM R Gunner
Apr 9, 2009·Proceedings of the National Academy of Sciences of the United States of America·Anurag SethiZaida Luthey-Schulten
Apr 11, 2009·Science·Robert G Smock, Lila M Gierasch
Aug 1, 2007·Journal of Applied Crystallography·Airlie J McCoyRandy J Read
Jan 9, 2010·Acta Crystallographica. Section D, Biological Crystallography·Vincent B ChenDavid C Richardson
Feb 18, 2010·Journal of Chemical Theory and Computation·Christopher L McClendonMatthew P Jacobson
Jun 2, 2010·Journal of Chemical Theory and Computation·Yilin Meng, Adrian E Roitberg
Jan 29, 2011·Proceedings of the National Academy of Sciences of the United States of America·Diego U FerreiroPeter G Wolynes
Apr 5, 2011·Acta Crystallographica. Section D, Biological Crystallography·Philip R Evans
Apr 5, 2011·Acta Crystallographica. Section D, Biological Crystallography·Garib N MurshudovAlexei A Vagin
May 26, 2012·Science·P Andrew Karplus, Kay Diederichs
Nov 10, 2012·Journal of Chemical Theory and Computation·Adam T VanwartRommie E Amaro
Jun 12, 2013·Protein Science : a Publication of the Protein Society·Penelope J CrossEmily J Parker
Jan 28, 2014·PLoS Computational Biology·Zoltan PalmaiErika Balog
Mar 29, 2014·Current Opinion in Structural Biology·Victoria A FeherRommie E Amaro
Apr 18, 2014·Nature·Hesam N MotlaghVincent J Hilser
Apr 30, 1998·The Journal of Physical Chemistry. B·A D MacKerellM Karplus

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Citations

Apr 26, 2016·The Journal of Physical Chemistry. B·Alexander K ClarkTongye Shen
Dec 20, 2017·Proceedings of the National Academy of Sciences of the United States of America·Giulio RagazzonAlberto Credi
Aug 10, 2016·The Journal of Biological Chemistry·Ali Reza NazmiEmily J Parker
Aug 3, 2020·Current Opinion in Structural Biology·Wanting JiaoEmily J Parker
Feb 6, 2021·Biochemical Society Transactions·Wanting Jiao
Aug 2, 2019·The Journal of Physical Chemistry. B·Jorge Enrique Hernández GonzálezVitor B P Leite

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