Water Dynamics around T0 vs. R4 of Hemoglobin from Local Hydrophobicity Analysis

TL;DR

This study uses molecular dynamics to compare local hydration and hydrophobicity around hemoglobin's T0 and R4 states, revealing differences in water structure and interface hydration relevant to allostery.

Contribution

It introduces a detailed analysis of local hydrophobicity at hemoglobin interfaces, contrasting it with solvent accessible surface area and highlighting hydration's role in allosteric transitions.

Findings

Water molecules at the interface increase by ~25% from T0 to R4.

Local hydrophobicity varies significantly for specific residues.

Correlation between LH and buried surface is moderate but improves with confidence intervals.

Abstract

The local hydration around tetrameric Hb in its T$_0$ and R$_4$ conformational substates is analyzed based on molecular dynamics simulations. Analysis of the local hydrophobicity (LH) for all residues at the $\alpha_1 \beta_2$ and $\alpha_2 \beta_1$ interfaces, responsible for the quaternary T$\rightarrow$R transition, which is encoded in the MWC model, as well as comparison with earlier computations of the solvent accessible surface area (SASA), makes clear that the two quantities measure different aspects of hydration. Local hydrophobicity quantifies the presence and structure of water molecules at the interface whereas ``buried surface'' reports on the available space for solvent. For simulations with Hb frozen in its T$_0$ and R$_4$ states the correlation coefficient between LH and buried surface is 0.36 and 0.44, respectively, but it increases considerably if the 95 \% confidence interval is used. The LH with Hb frozen and flexible changes little for most residues at the interfaces but is significantly altered for a few select ones, which are Thr41$\alpha$, Tyr42$\alpha$, Tyr140$\alpha$, Trp37$\beta$, Glu101$\beta$ (for T$_0$) and Thr38$\alpha$, Tyr42$\alpha$, Tyr140$\alpha$ (for R$_4$). The number of water molecules at the interface is found to increase by $\sim 25$ \% for T$_0$$\rightarrow$R$_4$ which is consistent with earlier measurements. Since hydration is found to be essential to protein function, it is clear that hydration also plays an essential role in allostery.