Paper Citing NAMD - Abstract
Zhao, Junjie; de Serrano, Vesna; Franzen, Stefan
A Model for the Flexibility of the Distal Histidine in Dehaloperoxidase-Hemoglobin A Based on X-ray Crystal Structures of the Carbon Monoxide Adduct
BIOCHEMISTRY, 53:2474-2482, APR 22 2014
Dehaloperoxidase hemoglobin A (DHP A) is a multifunctional hemoglobin that appears to have evolved oxidative pathways for the degradation of xenobiotics as a protective function that complements the oxygen transport function. DHP A possesses at least two internal binding sites, one for substrates and one for inhibitors, which include various halogenated phenols and indoles. Herein, we report the X-ray crystallographic structure of the carbonmonoxy complex (DHPCO). Unlike other DHP structures with 6-coordinated heme, the conformation of the distal histidine (HSS) in DHPCO is primarily external or solvent exposed, despite the fact that the heme Fe is 6-coordinated. As observed generally in globins, DHP exhibits two distal histidine conformations (one internal and one external). In previous structural studies, we have shown that the distribution of HSS conformations is weighted strongly toward the external position when the DHP heme Fe is 5-coordinated. The large population of the external conformation of the distal histidine observed in DHPCO crystals at pH 6.0 indicates that some structural factor in DHP must account for the difference from other globins, which exhibit a significant external conformation only when pH < 4.5. While the original hypothesis suggested that interaction with a heme-Fe-bound ligand was the determinant of HSS conformation, the current study forces a refinement of that hypothesis. The external or open conformation of HSS is observed to have interactions with two propionate groups in heme, at distances of 3.82 and 2.73 angstrom, respectively. A relatively weak hydrogen bonding interaction between HSS and CO, combined with strong interactions with heme propionate (position 6), is hypothesized to strengthen the external conformation of HSS. Density function theory (DFT) calculations were conducted to test whether there is a weaker hydrogen bond interaction between HSS and heme bonded CO or O-2. Molecular dynamics simulations were conducted to examine how the tautomeric forms of HSS affect the dynamic motions of the distal histidine that govern the switching between open and closed conformations. The calculations support the modified hypothesis suggesting a competition between the strength of interactions with heme ligand and the heme propionates as the factors that determine the conformation of the distal histidine.
