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

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

doi:10.7554/elife.35560

Krystel El Hage, Florent Hédin + Show 3 more

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https://doi.org/10.7554/elife.35560

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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[Formula: see text]) and liganded (R[Formula: see text]) tetramers are stable in solution, the published MD simulations of T[Formula: see text] undergo a rapid quaternary transition to an R-like structure. We show that T[Formula: see text] 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[Formula: see text] tetramer, to be manifested. Even in the largest box, T[Formula: see text] 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.

Highlights

Human hemoglobin is the paradigmatic model system for cooperativity in proteins
Wyman and Changeux formulated the allosteric (MWC) model (Monod et al, 1965; Cui and Karplus, 2008) based on the structural transition between two quaternary structures (T and R) to explain the indirect interaction between the heme groups required for cooperative oxygen binding
The instability of T0 in the published simulations raises a fundamental question: What is wrong with them? In search for an answer, we focused on the hydrophobic effect (Chothia et al, 1976; Lesk et al, 1985), which arises from the disruption of the bulk water hydrogen bond network around nonpolar groups (Rossky et al, 1979; Cheng and Rossky, 1998)

Summary

Introduction

Human hemoglobin is the paradigmatic model system for cooperativity in proteins. It transports oxygen from the lungs to the tissues and it is composed of two identical a-chains (a1 and a2) and two identical bÀchains (b1 and b2). It is interesting to note that the average number of hydrogen bonds per water molecule, /molecule (see Figure 3) shows such an effect: for the three smaller boxes the /molecule decreases by 10À3 to 10À4 with every transition.

Results

Conclusion