Tertiary and quaternary structural basis of oxygen affinity in human hemoglobin as revealed by multiscale simulations

CAPECE, LUCIANA; BRINGAS, MAURO; MARTÍ, MARCELO A.; ESTRIN, DARÍO A.; ESTRIN, DARÍO A.; PETRUK, ARIEL A.; MARTÍ, MARCELO A.; CAPECE, LUCIANA; PETRUK, ARIEL A.; BRINGAS, MAURO

Scientific Reports

Nature Publishing Group

Año: 2017 vol. 7 p. 10926 - 10926

Human hemoglobin (Hb) is a benchmark protein of structural biology that shaped our view of allosterism over 60 years ago, with the introduction of the MWC model based on Perutz structures of the oxy(R) and deoxy(T) states and the more recent Tertiary Two-State model that proposed the existence of individual subunit states -"r" and "t"-, whose structure is yet unknown. Cooperative oxygen binding is essential for Hb function, and despite decades of research there are still open questions related to how tertiary and quaternary changes regulate oxygen affinity. In the present work, we have determined the free energy profiles of oxygen migration and for HisE7 gate opening, with QM/MM calculations of the oxygen binding energy in order to address the influence of tertiary differences in the control of oxygen affinity. Our results show that in the α subunit the low to high affinity transition is achieved by a proximal effect that mostly affects oxygen dissociation and is the driving force of the allosteric transition, while in the β subunit the affinity change results from a complex interplay of proximal and distal effects, including an increase in the HE7 gate opening, that as shown by free energy profiles promotes oxygen uptake.