Abstract
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.
Highlights
A surprising effect of the simulation box size was recently reported for spontaneous hemoglobin transitions from the T to the R state in molecular dynamics simulations of deoxy hemoglobin (El Hage et al, 2018)
We present a systematic study of box size dependence in a variety of systems including hemoglobin, in which we observe no significant effect of the simulation box size on the kinetics or thermodynamics of conformational transitions
We find that in the 9 nm box a substantial fraction does not undergo the transition within 1 ms, rendering the absence of a transition in the single simulation of the 15 nm box in the El Hage et al (2018) study statistically insignificantly different from those observed for the 9 nm box
Summary
A surprising effect of the simulation box size was recently reported for spontaneous hemoglobin transitions from the T to the R state in molecular dynamics simulations of deoxy hemoglobin (El Hage et al, 2018). It was reported that the T state was stable for a period of 1 microsecond only in a relatively large simulation box with a cube edge length of 15 nm, whereas in smaller simulation boxes spontaneous transitions to the R state were observed on this timescale. We present a systematic study of box size dependence in a variety of systems including hemoglobin, in which we observe no significant effect of the simulation box size on the kinetics or thermodynamics of conformational transitions
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