Valid molecular dynamics simulations of human hemoglobin require a surprisingly large box size

ELife
Krystel El HageMartin Karplus

Abstract

Recent molecular dynamics (MD) simulations of human hemoglobin (Hb) give results in disagreement with experiment. Although it is known that the unliganded (T[Formula: see text]) and liganded (R[Formula: see text]) tetramers are stable in solution, the published MD simulations of T[Formula: see text] undergo a rapid quaternary transition to an R-like structure. We show that T[Formula: see text] is stable only when the periodic solvent box contains ten times more water molecules than the standard size for such simulations. The results suggest that such a large box is required for the hydrophobic effect, which stabilizes the T[Formula: see text] tetramer, to be manifested. Even in the largest box, T[Formula: see text] is not stable unless His146 is protonated, providing an atomistic validation of the Perutz model. The possibility that extra large boxes are required to obtain meaningful results will have to be considered in evaluating existing and future simulations of a wide range of systems.

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Citations

Mar 1, 2019·Chemphyschem : a European Journal of Chemical Physics and Physical Chemistry·Ran Friedman
Sep 1, 2019·The Journal of Chemical Physics·Rukmankesh Mehra, Kasper P Kepp
Feb 8, 2019·Physical Chemistry Chemical Physics : PCCP·Esther Heid, Daniel Braun
Sep 5, 2019·Current Pharmaceutical Design·Indrani Bera, Pavan V Payghan
Feb 6, 2020·American Journal of Physiology. Regulatory, Integrative and Comparative Physiology·Angela FagoJay F Storz
Oct 22, 2020·Communications Biology·Monica L Fernández-QuinteroKlaus R Liedl
Dec 18, 2020·Frontiers in Molecular Biosciences·Monica L Fernández-QuinteroKlaus R Liedl
Apr 8, 2020·Computational and Structural Biotechnology Journal·Eli Fernández-de GortariL Michel Espinoza-Fonseca
Jun 27, 2020·The Journal of Physical Chemistry. B·Marco PezzellaMartin Karplus
Mar 30, 2021·Philosophical Transactions. Series A, Mathematical, Physical, and Engineering Sciences·Shunzhou WanPeter V Coveney
Oct 19, 2020·Biophysical Journal·Olga N RaguimovaL Michel Espinoza-Fonseca
May 5, 2021·The Journal of Chemical Physics·Seyedeh Maryam Salehi, Markus Meuwly
Feb 20, 2021·Annual Review of Biophysics·Tamar SchlickEva Xue
May 8, 2021·Frontiers in Molecular Biosciences·Monica L Fernández-QuinteroKlaus R Liedl
Jul 20, 2021·Journal of Chemical Theory and Computation·Maxime VassauxPeter V Coveney
Aug 11, 2021·Journal of Chemical Information and Modeling·Nicole BalascoLuigi Vitagliano
Jun 28, 2019·Chemical Reviews·Emelie FloodToby W Allen
Apr 3, 2020·Journal of Chemical Information and Modeling·Gudrun Gygli, Juergen Pleiss
Jan 31, 2020·Journal of Chemical Theory and Computation·Matías R Machado, Sergio Pantano
Jan 9, 2022·Scientific Reports·Amanat AliRanjit Vijayan

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Methods Mentioned

BETA
X-ray

Software Mentioned

GROMACS
CHARMM36

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