Methemoglobin formation in mutant hemoglobin α chains: electron transfer parameters and rates

Area of Science:

• Biophysics
• Computational Chemistry
• Molecular Biology

Background:

• Hemoglobin's dioxygen transport relies on stable reduced heme (Fe2+).
• Mutations can stabilize oxidized heme (Fe3+), leading to methemoglobinemia, a potentially lethal condition.
• Previous studies primarily analyzed inner-sphere heme mutations.

Purpose of the Study:

• To investigate the impact of mutations on hemoglobin (Hb) oxidation and reduction rates using all-atom molecular dynamics simulations.
• To calculate Marcus electron transfer (ET) parameters for Hb wild-type (WT) and Hb M variants.
• To provide a mechanistic understanding of how mutations affect Hb stability and redox properties.

Main Methods:

• All-atom molecular dynamics simulations of Hb WT and α chain variants in both redox states.
• Calculation of Marcus electron transfer (ET) parameters.
• Analysis of heme-solvent hydrogen bonding interactions.

Main Results:

• Most Hb WT and α chain variants maintained globin structure, except Hb M Iwate (H87Y).
• Hb M variants exhibited lower redox potentials, stabilizing the Fe3+ state, notably Hb Miyagi (K61E).
• Solvent reorganization significantly contributed to free energy; protein reorganization varied, with Miyagi and J-Buda showing minimal contribution.
• Lys61 residue plays a role in stabilizing the Fe2+ state through heme-solvent H-bonding.

Conclusions:

• The developed methodology accurately predicts electron transfer rates and provides insights into mutation effects on Hb structure, stability, and redox properties.
• This approach can identify mutations leading to methemoglobinemia.
• Understanding these mechanisms is crucial for diagnosing and potentially treating methemoglobinemia.