We have studied the electrostatic effect of protein environment on electronic structures and chemical indices of the active site of oxygenated and deoxygenated hemerythrin (oxyHr and deoxyHr) using hybrid density functional calculations. We found that the UBHandHLYP method can be regarded as a reliable method for the nature of chemical bonds of Hr even in the protein. The electrostatic effects of the protein environment on oxyHr and deoxyHr greatly improve the magnetic couplings and provide the polarized electronic structures. The electrostatic effects on the active site of oxyHr hardly affect the shape and symmetry of singly occupied natural orbitals but contribute to the enhanced orbital interaction between the active core of Hr and oxygen molecule. This strong orbital interaction leads to easy binding of oxygen molecule to Hr for oxygen transport. Thus, our computation suggests that protein environment regulates the electronic structures of the active site to intensify the intrinsic ability of the active site and to express biological functions such as oxygen transport, energy conversion, and electron transfer. © 2012 Wiley Periodicals, Inc.