This Article Full Text Full Text (PDF) Supplemental Material Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Rinaldo, D. Articles by Field, M. J. Search for Related Content PubMed PubMed Citation Articles by Rinaldo, D. Articles by Field, M. J.

A Computational Study of the Open and Closed Forms of the N-Lobe Human Serum Transferrin Apoprotein

Laboratoire de Dynamique Moléculaire, Institut de Biologie Structurale Jean-Pierre Ebel, Commissariat à l'Energie Atomique, and the Centre National de Recherche Scientifique, Grenoble, France

Correspondence: Address reprint requests to Martin J. Field, Laboratoire de Dynamique Moléculaire, Institut de Biologie Structurale Jean-Pierre Ebel, 41 rue Jules Horowitz, 38027 Grenoble cedex 1, France. Tel.: 33-43-878-5919; Fax: 33-43-878-5122; E-mail: mjfield{at}ibs.fr.

Human serum transferrin tightly binds ferric ions in the blood stream but is able to release them in cells by a process involving receptor-mediated endocytosis and decrease in pH. Iron binding and release are accompanied by a large conformation change. In this study, we investigate theoretically the open and closed forms of the N-lobe human serum transferrin apoprotein by performing pK_a calculations and molecular dynamics and free-energy simulations. In agreement with the hypothesis based on the x-ray crystal structures, our calculations show that there is a shift in the pK_a values of the lysines forming the dilysine trigger when the conformation changes. We argue, however, that simple electrostatic repulsion between the lysines is not sufficient to trigger domain opening and, instead, propose an alternative explanation for the dilysine-trigger effect. Analysis of the molecular dynamics and free-energy results indicate that the open form is more mobile than the closed form and is much more stable at pH 5.3, in large part due to entropic effects. Despite a lower free energy, the dynamics simulation of the open form shows that it is flexible enough to sample conformations that are consistent with iron binding.

This article has been cited by other articles:

				J. D. Campbell, S. S. Deol, F. M. Ashcroft, I. D. Kerr, and M. S. P. Sansom Nucleotide-Dependent Conformational Changes in HisP: Molecular Dynamics Simulations of an ABC Transporter Nucleotide-Binding Domain Biophys. J., December 1, 2004; 87(6): 3703 - 3715. [Abstract] [Full Text] [PDF]