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

Krystel El Hage; Florent Hédin; Prashant K. Gupta; Markus Meuwly; Martin Karplus

doi:10.7554/eLife.35560

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

Krystel El Hage
, Florent Hédin
, Prashant K. Gupta
, Markus Meuwly
, Martin Karplus

University of Basel
Harvard University
Université de Strasbourg

Research output: Contribution to journal › Article › peer-review

78 Scopus citations

Abstract

Recent molecular dynamics (MD) simulations of human hemoglobin (Hb) give results in disagreement with experiment. Although it is known that the unliganded (T ₀ ) and liganded (R ₄ ) tetramers are stable in solution, the published MD simulations of T ₀ undergo a rapid quaternary transition to an R-like structure. We show that T ₀ 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 ₀ tetramer, to be manifested. Even in the largest box, T ₀ 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.

Original language	English
Article number	e35560
Journal	eLife
Volume	7
DOIs	https://doi.org/10.7554/eLife.35560
State	Published - 12 Jul 2018
Externally published	Yes

Bibliographical note

Publisher Copyright:
© El Hage et al.

Funding

We thank David Chandler†, to whom we dedicate this paper, for many fruitful discussions. The work in Switzerland was supported by the Swiss National Science Foundation through grants 200021– 117810, and the NCCR MUST. The work at Harvard was supported in part by the CHARMM Development Project.

Funders	Funder number
NCCR MUST
Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung	200021– 117810

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10.7554/eLife.35560

Cite this

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abstract = " Recent molecular dynamics (MD) simulations of human hemoglobin (Hb) give results in disagreement with experiment. Although it is known that the unliganded (T 0 ) and liganded (R 4 ) tetramers are stable in solution, the published MD simulations of T 0 undergo a rapid quaternary transition to an R-like structure. We show that T 0 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 0 tetramer, to be manifested. Even in the largest box, T 0 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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AU - Karplus, Martin

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

Abstract

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