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Biophys J, October 2001, p. 1938-1946, Vol. 81, No. 4

Molecular Dynamics Analysis of a Second Phosphate Site in the Hemoglobins of the Seabird, South Polar Skua. Is There a Site-Site Migratory Mechanism along the Central Cavity?

Antonio Riccio,* Maurizio Tamburrini,* Bruno Giardina,dagger and Guido di Prisco*

 *Institute of Protein Biochemistry and Enzymology, C.N.R., I-80125 Naples, Italy; and  dagger Institute of Chemistry and Clinical Chemistry, Faculty of Medicine, Catholic University "Sacro Cuore," I-00168 Rome, Italy

Hemoglobin function is modulated by several non-heme ligands; among these effectors, organic phosphates generally bind to heterotropic sites with a one-to-one stoichiometry. The phosphate binding site of human hemoglobin is located at the interface between the two beta  chains. An additional binding site for polyanions has been studied at the molecular level (Tamburrini, M., A. Riccio, M. Romano, B. Giardina, and G. di Prisco. 2000. Eur. J. Biochem. 267:6089-6098) in the hemoglobins of the south polar skua (Catharacta maccormicki). It is formed by a cluster of six positive charges of both alpha  chains (Val-1, Lys-99, Arg-141); the two Lys-99alpha have an essential role in the site structure. The present investigation, carried out on skua deoxyhemoglobins by using a molecular dynamics approach, confirms the structural feasibility of the additional site, possibly having the role of an entry-leaving site, and leads to the proposal of a novel migration pathway for phosphate along the central cavity of hemoglobin from one binding site to the other, occurring according to the hypothesis of a site-site migratory mechanism, which may assign a functional role to the central cavity. The role of Lys-99alpha was further confirmed by molecular dynamics experiments on the mutant Lys-99alpha right-arrowAla in which, at the end of the simulation, the phosphate was external to the additional site.

Biophys J, October 2001, p. 1938-1946, Vol. 81, No. 4
© 2001 by the Biophysical Society   0006-3495/01/10/1938/09  $2.00


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