1. Structural Biology and Molecular Biophysics

On the importance of statistics in molecular simulations for thermodynamics, kinetics and simulation box size

  1. Vytautas Gapsys
  2. Bert L de Groot  Is a corresponding author
  1. Max-Planck Institute for Biophysical Chemistry, Germany
https://doi.org/10.7554/eLife.57589
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  1. Vytautas Gapsys
  2. Bert L de Groot
(2020)
On the importance of statistics in molecular simulations for thermodynamics, kinetics and simulation box size
eLife 9:e57589.
https://doi.org/10.7554/eLife.57589
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Abstract

Computational simulations, akin to wetlab experimentation, are subject to statistical fluctuations. Assessing the magnitude of these fluctuations, i.e. assigning uncertainties to the computed results, is of critical importance to drawing statistically reliable conclusions. Here, we use a simulation box size as an independent variable, to demonstrate how crucial it is to gather sufficient amounts of data before drawing any conclusions about the potential thermodynamic and kinetic effects. In various systems, ranging from solvation free energies to protein conformational transition rates, we showcase how the proposed simulation box size effect disappears with increased sampling. This indicates that, if at all, the simulation box size only minimally affects both the thermodynamics and kinetics of the type of biomolecular systems presented in this work.

Data availability

Input files and data for all the figures is provided: 10.5281/zenodo.3959198

The following data sets were generated

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Author details

  1. Vytautas Gapsys

    Computational Biomolecular Dynamics Group, Max-Planck Institute for Biophysical Chemistry, Göttingen, Germany
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-6761-7780

  2. Bert L de Groot

    Computational Biomolecular Dynamics Group, Max-Planck Institute for Biophysical Chemistry, Göttingen, Germany
    For correspondence
    bgroot@gwdg.de
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3570-3534

Funding

European Commission (H2020-EINFRA-2015-1-675728)

  • Vytautas Gapsys
  • Bert L de Groot

European Commission (H2020-INFRAEDI-02-2018-823830)

  • Vytautas Gapsys
  • Bert L de Groot

Max-Planck-Gesellschaft

  • Bert L de Groot

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Copyright

© 2020, Gapsys & de Groot

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Vytautas Gapsys
  2. Bert L de Groot
(2020)
On the importance of statistics in molecular simulations for thermodynamics, kinetics and simulation box size
eLife 9:e57589.
https://doi.org/10.7554/eLife.57589

Share this article

https://doi.org/10.7554/eLife.57589

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Further reading

    1. Structural Biology and Molecular Biophysics

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

    Vytautas Gapsys, Bert L de Groot
    Scientific Correspondence

    A recent molecular dynamics investigation into the stability of hemoglobin concluded that the unliganded protein is only stable in the T state when a solvent box is used in the simulations that is ten times larger than what is usually employed (El Hage et al., 2018). Here, we express three main concerns about that study. In addition, we find that with an order of magnitude more statistics, the reported box size dependence is not reproducible. Overall, no significant effects on the kinetics or thermodynamics of conformational transitions were observed.

    1. Computational and Systems Biology
    2. Structural Biology and Molecular Biophysics

    Response to comment on 'Valid molecular dynamics simulations of human hemoglobin require a surprisingly large box size'

    Krystel El Hage, Florent Hédin ... Martin Karplus
    Scientific Correspondence

    We recently reported that molecular dynamics simulations for hemoglobin require a surprisingly large box size to stabilize the T(0) state relative to R(0), as observed in experiments (El Hage et al., 2018). Gapsys and de Groot have commented on this work but do not provide convincing evidence that the conclusions of El Hage et al., 2018 are incorrect. Here we respond to these concerns, argue that our original conclusions remain valid, and raise our own concerns about some of the results reported in the comment by Gapsys and de Groot that require clarification.

    1. Structural Biology and Molecular Biophysics

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

    Krystel El Hage, Florent Hédin ... Martin Karplus
    Research Article

    Recent molecular dynamics (MD) simulations of human hemoglobin (Hb) give results in disagreement with experiment. Although it is known that the unliganded (T0) and liganded (R4) tetramers are stable in solution, the published MD simulations of T0 undergo a rapid quaternary transition to an R-like structure. We show that T0 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 T0 tetramer, to be manifested. Even in the largest box, T0 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.