Non-site-specific allosteric effect of oxygen on human hemoglobin under high oxygen partial pressure

Protein allostery is essential for vital activities. Allosteric regulation of human hemoglobin (HbA) with two quaternary states T and R has been a paradigm of allosteric structural regulation of proteins. It is widely accepted that oxygen molecules (O-2) act as a "site-specific'' homotropic effector, or the successive O-2 binding to the heme brings about the quaternary regulation. However, here we show that the site-specific allosteric effect is not necessarily only a unique mechanism of O-2 allostery. Our simulation results revealed that the solution environment of high O-2 partial pressure enhances the quaternary change from T to R without binding to the heme, suggesting an additional "non-site-specific'' allosteric effect of O-2. The latter effect should play a complementary role in the quaternary change by affecting the intersubunit contacts. This analysis must become a milestone in comprehensive understanding of the allosteric regulation of HbA from the molecular point of view.