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Sulfide-Binding Hemoglobins: Effects of Mutations on Active-Site Flexibility

S. Fernandez-Alberti ^*, D. E. Bacelo  , R. C. Binning, Jr. , J. Echave ^* , M. Chergui ^¶ and J. Lopez-Garriga ^||

^* Universidad Nacional de Quilmes, 1876 Bernal, Argentina; Department of Science and Technology, Universidad Metropolitana, San Juan, Puerto Rico 00928-1150; Departamento de Química, Universidad Nacional de la Patagonia SJB, Ciudad Universitaria, Argentina; INIFTA, 1900 La Plata, Buenos Aires, Argentina; ^¶ Laboratoire de Spectroscopie, Institut des Sciences et Ingénierie Chimiques, Faculté des Sciences de Base, Ecole Polytechnique Fédérale de Lausanne, Lausanne-Dorigny, CH-1015 Lausanne-Dorigny, Switzerland; and ^|| Department of Chemistry, University of Puerto Rico, Mayagüez Campus, Mayagüez, Puerto Rico 00681-9019

Correspondence: Address reprint requests to Sebastián Fernandez-Alberti, E-mail: seba{at}unq.edu.ar.

The dynamics of Hemoglobin I (HbI) from the clam Lucina pectinata, from wild-type sperm whale (SW) myoglobin, and from the L29F/H64Q/V68F triple mutant of SW, both unligated and bound to hydrogen sulfide (H₂S), have been studied in molecular dynamics simulations. Features that account for differences in H₂S affinity among the three have been examined. Our results verify the existence of an unusual heme rocking motion in unligated HbI that can promote the entrance of large ligands such as H₂S. The FQF-mutant partially reproduces the amplitude and relative orientation of the motion of HbI's heme group. Therefore, besides introducing favorable electrostatic interactions with H₂S, the three mutations in the distal pocket change the dynamic properties of the heme group. The active-site residues Gln-64(E7), Phe-43(CD1), and His-93(F8) are also shown to be more flexible in unligated HbI than in FQF-mutant and SW. Further contributions to H₂S affinity come from differences in hydrogen bonding between the heme propionate groups and nearby amino acid residues.

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