The Functional Role of the Hemoglobin-Water Interface

TL;DR

This paper reviews experimental and computational studies on hemoglobin's water interface, highlighting how water influences hemoglobin stability and function, and discusses future challenges in simulating crowded cellular environments.

Contribution

It combines experimental and molecular dynamics simulation results to elucidate the role of water in hemoglobin stability and function, emphasizing the importance of simulation box size and cellular conditions.

Findings

Hydrophobic effect influences hemoglobin stability in large simulation boxes.

Molecular dynamics provide insights into the Perutz model of hemoglobin function.

Experimental data support the significance of water in physiological conditions.

Abstract

The interface between hemoglobin (Hb) and its environment, in particular water, is of great physiological relevance. Here, results from {\it in vitro}, {\it in vivo}, and computational experiments (molecular dynamics simulations) are summarized and put into perspective. One of the main findings from the computations is that the stability of the deoxy, ligand-free T-state (T$_0$) can be stabilized relative to the deoxy R-state (R$_0$) only in sufficiently large simulation boxes for the hydrophobic effect to manifest itself. This effect directly influences protein stability and is operative also under physiological conditions. Furthermore, molecular simulations provide a dynamical interpretation of the Perutz model for Hb function. Results from experiments using higher protein concentrations and realistic cellular environments are also discussed. One of the next great challenges for computational studies, which as we show is likely to be taken up in the near future, is to provide molecular-level understanding of the dynamics of proteins in such crowded environments.