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J. Biol. Chem., Vol. 279, Issue 29, 30523-30530, July 16, 2004

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Characterization of the Conformational State and Flexibility of HIV-1 Glycoprotein gp120 Core Domain^*

Yongping Pan, Buyong Ma, Ozlem Keskin, and Ruth Nussinov, Supported in part by the Center of Excellence in Geometric Computing and its Applications funded by the Israel Science Foundation administered by the Israel Academy of Sciences¶||

From the Basic Research Program, Science Applications International Corporation-Frederick, Inc., Laboratory of Experimental and Computational Biology, NCI-Frederick, National Institutes of Health, Frederick, Maryland 21702, the Koc University, Center for Computational Biology and Bioinformatics and College of Engineering, Rumelifeneri Yolu, 34450 Sariyer Istanbul, Turkey, and the ^¶Sackler Institute of Molecular Medicine, Department of Human Genetics and Molecular Medicine, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel

gp120 is key to the human immunodeficiency virus type 1 viral cell entry. Knowledge of the detailed conformational states of gp120 is crucial to intervention, yet the unbound form is still resistant to structural characterization probably because of its flexibility. Toward this goal, we performed molecular dynamics simulations on the wild type gp120 core domain extracted from its ternary crystal structure and on a modeled mutant, S375W, that experimentally has a significantly different phenotype from the wild type. Although the mutant retained a bound-like conformation, the wild type drifted to a different conformational state. The wild type strands 2 and 3 of the bridging sheet were very mobile and partially unfolded, and the organization among the inner and outer domains and strands 20 and 21 of the bridging sheet, near the mutation site, was more open than in the bound form, although the overall structure was maintained. These differences were apparently a result of the strengthening of the hydrophobic core in the mutant. This stabilization further explains the experimentally significantly different thermodynamic properties between the wild type and the mutant. Taken together, our results suggest that the free form, although different from the bound state, shares many of the bound structural features. The observed loss of freedom near the binding site, rather than the previously hypothesized more dramatic conformational transition from the unbound to the bound state, appears to be the major contributor to the large entropy cost for the CD4 binding to the wild type.

Received for publication, April 20, 2004 , and in revised form, May 6, 2004.

^* This work was supported in whole or in part with federal funds from the NCI, National Institutes of Health, under Contract Number NO1-CO-12400. 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.

^|| To whom correspondence should be addressed: NCI-Frederick, Bldg. 469, Rm. 151, Frederick, MD 21702. Tel.: 301-846-5579; Fax: 301-846-5598; E-mail: ruthn{at}ncifcrf.gov.

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