Heme isomers substantially affect heme's electronic structure and function.

Area of Science:

• Biochemistry
• Computational Chemistry
• Structural Biology

Background:

• Heme proteins are vital biological molecules involved in oxygen transport and enzymatic catalysis.
• The protein data bank contains diverse heme protein structures, yet the isomeric forms of heme itself have not been fully explored.

Purpose of the Study:

• To investigate the structural and electronic implications of different heme isomers in various heme protein environments.
• To determine the functional consequences of heme isomerism on key properties like oxygen binding and redox potential.

Main Methods:

• Analysis of heme protein structures from the Protein Data Bank.
• Density functional theory (DFT) computations to assess isomer energies, interconversion barriers, and electronic properties.
• Investigation of four heme isomers (EE, EZ, ZE, ZZ) in different coordination states (4-, 5-, and 6-coordinate) and functional contexts (e.g., oxygen adducts, compound I).

Main Results:

• Four heme isomers with distinct vinyl side chain orientations exist and are found in known protein structures.
• DFT calculations reveal similar isomer energies but a significant interconversion barrier, explaining their prevalence.
• Heme isomerism substantially influences electronic properties, including O2-heme adduct spin state energy gaps, O2-binding enthalpies, redox potentials, and compound I doublet-quartet splitting.

Conclusions:

• Heme isomerism is a critical, yet often overlooked, factor affecting heme protein function.
• The specific isomer state of heme can modulate key functional parameters, impacting oxygen affinity and enzymatic reactivity.
• Future studies on heme chemistry and function should consider the influence of these distinct heme isomer states.