On the importance of statistics in molecular simulations for thermodynamics, kinetics and simulation box size
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
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Input files and data for the publicationZenodo, doi:10.5281/zenodo.3959198.
Article and author information
Author details
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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Further reading
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- Computational and Systems Biology
- Structural Biology and Molecular Biophysics
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.
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- Structural Biology and Molecular Biophysics
Recent molecular dynamics (MD) simulations of human hemoglobin (Hb) give results in disagreement with experiment. Although it is known that the unliganded (T) and liganded (R) tetramers are stable in solution, the published MD simulations of T undergo a rapid quaternary transition to an R-like structure. We show that T 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 tetramer, to be manifested. Even in the largest box, T 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.