Identification of histidine residues that affect the T/R-state conformations of human hemoglobin using constant pH molecular dynamics simulations

• Published in: International journal of biological macromolecules Vol. 267; no. Pt 1; p. 131457
• Main Authors: Fujiwara, Shin-ichi, Nishimura, Kotaro, Imamura, Kazuto, Amisaki, Takashi
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.05.2024
• Subjects: Acid dissociation constant; Heme - chemistry; Hemoglobin; Hemoglobins - chemistry; Histidine; Histidine - chemistry; Humans; Hydrogen Bonding; Hydrogen-Ion Concentration; Molecular Dynamics Simulation; Protein Conformation; Protonation state; Protons; Hemoglobin; pH; Histidine; Molecular dynamics simulation; Acid dissociation constant; Protonation state
• ISSN: 0141-8130; 1879-0003
• DOI: 10.1016/j.ijbiomac.2024.131457

Human hemoglobin (Hb) is a tetrameric protein consisting of two α and two β subunits that can adopt a low-affinity T- and high-affinity R-state conformations. Under physiological pH conditions, histidine (His) residues are the main sites for proton binding or release, and their protonation states can affect the T/R-state conformation of Hb. However, it remains unclear which His residues can effectively affect the Hb conformation. Herein, the impact of the 38 His residues of Hb on its T/R-state conformations was evaluated using constant-pH molecular dynamics (CpHMD) simulations at physiological pH while focusing on the His protonation states. Overall, the protonation states of some His residues were found to be correlated with the Hb conformation state. These residues were mainly located in the proximity of the heme (α87 and β92), and at the α1β2 and α2β1 interfaces (α89 and β97). This correlation may be partly explained by how easily hydrogen bonds can be formed, which depends on the protonation states of the His residues. Taken together, these CpHMD-based findings provide new insights into the identification of titratable His residues α87, α89, β92, and β97 that can affect Hb conformational switching under physiological pH conditions. •Constant pH molecular dynamics simulations of Hb were performed.•Impact of the His protonation state on Hb conformation was analyzed.•Some His protonation states are correlated with Hb conformation.•The His residues are mainly proximal to the heme and at the α–β interface.