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Volume 272, Number 42, Issue of October 17, 1997 pp. 26271-26278
©1997 by The American Society for Biochemistry and Molecular Biology, Inc.

Modification of -Chain or -Chain Heme Pocket Polarity by Val(E11)  Thr Substitution Has Different Effects on the Steric, Dynamic, and Functional Properties of Human Recombinant Hemoglobin
DEOXY DERIVATIVES

(Received for publication, May 29, 1997, and in revised form, August 7, 1997)

From the Istituto Nazionale di Fisica della Materia (INFM) and Istituto di Fisica dell'Università, 90123 Palermo, Italy

Fred K. Friedman and Aditya P. Koley

From the Laboratory of Molecular Carcinogenesis, NCI, National Institutes of Health, Bethesda, Maryland 20892

Gregory B. Vasquez

From the Center for Advanced Research in Biotechnology of the University of Maryland Biotechnology Institute, Rockville, Maryland 20850

William S. Brinigar

From the Department of Chemistry, Temple University, Philadelphia, Pennsylvania 19122

Michael Karavitis and Clara Fronticelli

From the Department of Biochemistry and Molecular Biology, University of Maryland Medical School, Baltimore, Maryland 21201

The dynamic and functional properties of mutant deoxyhemoglobins in which either the -globin Val⁶⁷(E11) or the -globin Val⁶²(E11) is replaced by threonine have been investigated through the thermal evolution of the Soret absorption band in the temperature range 300 to 20 K and through the kinetics of CO rebinding after flash photolysis at room temperature. The conformational properties of the modified  chain and  chain distal heme pockets were also studied through x-ray crystallography and molecular modeling. The data obtained with the various techniques consistently indicate that the polar isosteric mutation in the distal side of the chain heme pocket has a larger effect on the investigated properties than the analogous mutation on the  chain. We attribute the observed differences to the presence of a water molecule in the distal heme pocket of the modified  chains, interacting with the hydroxyl of the threonine side chain. This is indicated by molecular modeling which showed that the water molecule present in the  chain distal heme pocket can bridge by H bonding between Thr⁶²(E11) and His⁵⁸(E7) without introducing any unfavorable steric interactions. Consistent with the dynamic and functional data, the presence of a water molecule in the distal heme pocket of the modified  chains is not observed by x-ray crystallography.

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