Histidine Protonation States Regulate the State Transition from R State Hemoglobin

Area of Science:

• Biochemistry
• Molecular Biology
• Biophysics

Background:

• The Bohr effect describes hemoglobin's O₂ affinity modulation by pH.
• Hemoglobin structural transitions are crucial for oxygen transport.
• Protonation of specific histidine residues influences these transitions.

Purpose of the Study:

• To investigate pH-induced structural changes in hemoglobin.
• To elucidate the role of histidine protonation states (PSs) in hemoglobin's R and R2 states.
• To understand the molecular mechanisms underlying the Bohr effect.

Main Methods:

• Molecular dynamics (MD) simulations were employed.
• Simulations explored hemoglobin transitions between R and R2 states.
• Investigated effects of varying pH (7.0, 6.5, 5.5) on histidine residue protonation.

Main Results:

• Protonated histidine residues promote R to R2 state transition.
• Increased distance between β1-β2 subunits observed due to weakened inter-subunit interactions.
• Protonation effects align with experimental observations of R2 state crystallization at low pH.

Conclusions:

• Protonation of βHis143 and βHis146 is key to pH-dependent hemoglobin structural changes.
• The interplay between protonation states and R state stability governs the Bohr effect.
• Findings provide molecular insights into hemoglobin's physiological oxygen transport regulation.