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

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

doi:10.7554/elife.45318

Krystel El Hage, Markus Meuwly + Show 3 more

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https://doi.org/10.7554/elife.45318

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Abstract

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.

Highlights

Our investigation of the box size dependence of hemoglobin in solution was initiated by the disagreement between the experimentally observed stabilization of the unliganded T state relative to an R-like structure (Edelstein, 1971), and molecular dynamics simulations which found that the unliganded T state (T(0)) was not stable and made a transition to an R-like state in times on the order of a hundred nanoseconds (Hub et al, 2010; Yusuff et al, 2012)
Proteins simulated under periodic boundary conditions, it has been found that the box type can have a statistically significant effect on the outcome of a simulation, and that the magnitude of the effect depends on the protein considered (Wassenaar and Mark, 2006). All of the latter may contribute to the difference in the results, we believe that a possible difference in the His protonation states used in the simulations would play a major role and needs to be examined
We believe we have demonstrated that the details of our simulations provide evidence that there is a box size dependence in hemoglobin simulations and that it is likely, though not proved, that in a 150 Abox the unliganded T state is stable

Summary

Introduction

Our investigation of the box size dependence of hemoglobin in solution was initiated by the disagreement between the experimentally observed stabilization of the unliganded T state relative to an R-like structure (Edelstein, 1971), and molecular dynamics simulations which found that the unliganded T state (T(0)) was not stable and made a transition to an R-like state in times on the order of a hundred nanoseconds (Hub et al, 2010; Yusuff et al, 2012). We began research to determine what could be wrong with the published simulations and found, after looking at many possibilities, that only a surprisingly large (150 A ) simulation box was able to stabilize the T(0) over at least ~1.3 microseconds (El Hage et al, 2018; Figure 1)

Results

Conclusions

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