Can All-Atom Molecular Dynamics Simulations Quantitatively Describe Homeodomain-DNA Binding Equilibria?

Journal of Chemical Theory and Computation
David Jakubec, Jiří Vondrášek

Abstract

We systematically investigate the applicability of a molecular dynamics-based setup for the calculations of standard binding free energies of biologically relevant protein-DNA complexes. The free energies are extracted from a potential of mean force calculated using umbrella sampling simulations. Two protein-DNA systems derived from a homeodomain transcription factor complex are studied in order to investigate the binding of both disordered and globular proteins. Free energies and trajectories obtained using two modern molecular mechanical force fields are compared to each other and to experimental data. The temperature dependence of the calculated standard binding free energies is investigated by performing all simulations over a range of temperatures. We show that the values of standard binding free energies obtained from these simulations are overestimated compared to experimental results. Significant differences are observed between the two protein-DNA systems and between the two force fields, which are explained by different propensities to form inter- and intramolecular contacts. The number of protein-DNA contacts increases with increasing temperature, in agreement with the experimentally known temperature dependence of e...Continue Reading

References

Jan 16, 1986·Nature·D Eisenberg, A D McLachlan
Aug 11, 1995·Journal of Molecular Biology·D H TsaoJ A Ferretti
Aug 30, 1994·Proceedings of the National Academy of Sciences of the United States of America·Z ShangC Abate
Feb 1, 1996·Journal of Molecular Graphics·W HumphreyK Schulten
Sep 15, 1996·Developmental Biology·R P Harvey
Jun 5, 1999·Journal of Molecular Biology·J M GruschusJ A Ferretti
Dec 11, 1999·Nucleic Acids Research·H M BermanP E Bourne
Apr 24, 2002·Physical Review. E, Statistical Physics, Plasmas, Fluids, and Related Interdisciplinary Topics·G E Crooks
Nov 25, 2003·Nature Structural Biology·Helen BermanHaruki Nakamura
Oct 7, 2004·Biophysical Journal·Michael Slutsky, Leonid A Mirny
Jun 1, 2005·Pharmacology & Therapeutics·Hiroshi Akazawa, Issei Komuro
Nov 15, 2005·Biophysical Journal·Michael S Lee, Mark A Olson
Jan 4, 2006·Biochemistry·Anatoly I DraganPeter L Privalov
Oct 24, 2006·Journal of Molecular Biology·Peter L PrivalovConceição A S A Minetti
Jan 11, 2007·The Journal of Chemical Physics·Giovanni BussiMichele Parrinello
Nov 8, 2007·Journal of the American Chemical Society·Alberto PérezModesto Orozco
Apr 17, 2008·The Journal of Chemical Physics·Eric DarveAndrew Pohorille
Jan 17, 2009·The Journal of Physical Chemistry. B·Yuqing Deng, Benoît Roux
Apr 14, 2009·Current Opinion in Structural Biology·Remo RohsBarry Honig
Oct 30, 2009·Nature·Remo RohsBarry Honig
Nov 19, 2009·Journal of the American Chemical Society·Agnes Tóth-PetróczyYaakov Levy
Dec 5, 2009·Journal of Molecular Biology·Dana VuzmanYaakov Levy
Dec 25, 2009·Journal of Computational Chemistry·Clara D ChristWilfred F van Gunsteren
Jan 9, 2010·The Journal of Physical Chemistry. B·Justin A Lemkul, David R Bevan
Mar 26, 2010·Annual Review of Biochemistry·Remo RohsRichard S Mann
Aug 13, 2010·The Journal of Physical Chemistry. B·Andrew PohorilleChristophe Chipot
Nov 17, 2010·Proceedings of the National Academy of Sciences of the United States of America·Dana Vuzman, Yaakov Levy
May 31, 2011·Trends in Biochemical Sciences·Monika FuxreiterSarah Bondos
Jul 9, 2011·Nucleic Acids Research·Daniel SeeligerHelmut Grubmüller
Aug 13, 2011·Accounts of Chemical Research·Alberto PérezModesto Orozco
Mar 1, 2012·Journal of Chemical Theory and Computation·Katarina HartAlexander D Mackerell
Apr 27, 2012·IUBMB Life·Rita Pancsa, Monika Fuxreiter
Aug 2, 2012·Biochemistry·Lagnajeet PradhanHyun-Joo Nam
May 30, 2013·The Journal of Physical Chemistry. B·Yoshiteru Yonetani, Hidetoshi Kono
Jun 25, 2013·Journal of Chemical Theory and Computation·James C GumbartChristophe Chipot
Apr 30, 1998·The Journal of Physical Chemistry. B·A D MacKerellM Karplus
Sep 16, 2014·Biochimica Et Biophysica Acta·Rodrigo Galindo-MurilloThomas E Cheatham
Oct 22, 2014·Methods in Molecular Biology·Vytautas GapsysHadas Leonov
Oct 16, 2015·Chromosoma·Thomas R Bürglin, Markus Affolter
Nov 17, 2015·Nature Methods·Ivan IvaniModesto Orozco
Nov 18, 2015·Journal of Chemical Theory and Computation·James A MaierCarlos Simmerling
Nov 19, 2015·Journal of Chemical Theory and Computation·M KreplJ Sponer
Jun 14, 2011·Journal of Chemical Theory and Computation·Ignasi BuchGianni De Fabritiis

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Citations

Jul 19, 2020·Current Opinion in Structural Biology·Jejoong YooAleksei Aksimentiev
Mar 27, 2020·Journal of Chemical Theory and Computation·David Jakubec, Jiří Vondrášek

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