Identification of possible kinetically significant anion-binding sites in human serum transferrin using molecular modeling strategies

Certain anions have been shown experimentally to influence the rate of iron release from human serum transferrin (HST), implying the existence of one or more allosteric kinetically significant anion‐binding (KISAB) sites on or near the surface of the protein. A rank‐ordered selection of potential HS...

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Bibliographic Details
Published in:Biopolymers 2004-02, Vol.73 (2), p.205-215
Main Authors: Amin, Elizabeth Ambrose, Harris, Wesley R., Welsh, William J.
Format: Article
Language:English
Subjects:
Anions - chemistry
Anions - metabolism
Binding Sites
Chlorides - chemistry
Chlorides - metabolism
Ferric Compounds - chemistry
Ferric Compounds - metabolism
human serum transferrin
Humans
iron-release kinetics
kinetically significant anion-binding sites
Kinetics
Models, Molecular
molecular dynamics
molecular mechanics
molecular modeling
Perchlorates - chemistry
Perchlorates - metabolism
Recombinant Proteins - chemistry
Solvents - chemistry
Sulfates - chemistry
Sulfates - metabolism
Thermodynamics
Transferrin - chemistry
Transferrin - genetics
Transferrin - metabolism
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Summary:Certain anions have been shown experimentally to influence the rate of iron release from human serum transferrin (HST), implying the existence of one or more allosteric kinetically significant anion‐binding (KISAB) sites on or near the surface of the protein. A rank‐ordered selection of potential HST KISAB sites has been obtained using a novel three‐stage molecular modeling strategy. The crystal structure of HST (1A8E.pdb) was first subjected to a heuristic analysis, in which positively charged and hydrogen‐bonding residues on or near the surface of the protein were identified. In this stage, a preliminary electrostatic potential map was also calculated, yielding six preliminary sites. Next, energy‐grid calculations were conducted in order to identify anion–protein interaction energy minima, which resulted in the inclusion of three additional sites. Finally, three anions already shown experimentally to demonstrate varied effects on HST iron‐release kinetics were placed at each potential site; molecular dynamics and molecular mechanics calculations were performed in order to elucidate the hydrogen‐bonding environment around each anion of the protein as well as to calculate anion–protein‐binding energies. © 2003 Wiley Periodicals, Inc. Biopolymers 73: 205–215, 2004
ISSN:0006-3525
1097-0282
DOI:10.1002/bip.10551