Computational Investigation of Protein Chemistry: “S-Nitrosohemoglobin”

Reliable computational studies of large biological systems have only recently become possible due to the availability of high-performance computing resources. In this contribution, we present large-scale quantum mechanics / molecular mechanics (QM/MM) studies of hemoglobin (Hb) and its derivatives. In recent years, Hb has been reported to play an important role in blood-flow regulation via its reactions with the vasodilator, nitric oxide (NO). "S-nitrosohemoglobin" (SNO-Hb) has then emerged as a key player. However, NO-derivatization of the conserved cysteine residue (Cysbeta93) of Hb has been proposed to yield either an S-nitrosothiol (RSNO), an S-hydroxyamino radical (RSN*OH) or a thionitroxide radical (RSNHO*). The relative stabilities of the different proposed chemical forms of "SNO-Hb" are being examined using large-scale QM/MM simulations, and the critical role of the protein environment in the relative stabilities of the "SNO-Hb" forms is demonstrated. Furthermore, it has been proposed that NO is first attached to the heme iron of the beta subunit of hemoglobin, and it is then displaced from the iron by the presence of molecular oxygen and transported to the Cysbeta93 residue. We also investigate the possible transport channels of NO from the heme to this cysteine residue.