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J. Biol. Chem., Vol. 283, Issue 35, 24155-24166, August 29, 2008

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CXC and CC Chemokines Form Mixed Heterodimers

ASSOCIATION FREE ENERGIES FROM MOLECULAR DYNAMICS SIMULATIONS AND EXPERIMENTAL CORRELATIONS^*

Irina V. Nesmelova, Yuk Sham, Jiali Gao^¶||, and Kevin H. Mayo^¶1

From the Department of Biochemistry, Molecular Biology, and Biophysics, Center for Drug Design, ^¶Supercomputing Institute, and ^||Department of Chemistry, University of Minnesota, Minneapolis, Minnesota 55455

CXC and CC chemokines are involved in numerous biological processes, and their function in situ may be significantly influenced by heterodimer formation, as was recently reported, for example, for CXC chemokines CXCL4/PF4 and CXCL8/IL8 that interact to form heterodimers that modulate chemotactic and cell proliferation activities. Here we used molecular dynamics simulations to determine relative association free energies (overall average and per residue) for homo- and heterodimer pairs of CXC (CXCL4/PF4, CXCL8/IL8, CXCL1/Gro-, and CXCL7/NAP-2) and CC (CCL5/RANTES, CCL2/MCP-1, and CCL8/MCP-2) chemokines. Even though structural homology among monomer folds of all CXC and CC chemokines permits heterodimer assembly, our calculated association free energies depend upon the particular pair of chemokines in terms of the net electrostatic and nonelectrostatic forces involved, as well as (for CC/CXC mixed chemokines) the selection of dimer type (CC or CXC). These relative free energies indicate that association of some pairs of chemokines is more favorable than others. Our approach is validated by correlation of calculated and experimentally determined free energies. Results are discussed in terms of CXC and CC chemokine function and have significant biological implications.

Received for publication, April 30, 2008 , and in revised form, June 5, 2008.

^* This work was supported, in whole or in part, by National Institutes of Health NRSA training Grant HL 07062 (to I. V. N.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. 1 and 2.

¹ To whom correspondence should be addressed: 6-155 Jackson Hall, University of Minnesota, 321 Church St., Minneapolis, MN 55455. Tel.: 612-625-9968; Fax: 612-624-5121; E-mail: mayox001{at}umn.edu.

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