Book of Abstracts: Albany 2007
June 19-23 2007
Structural Flexibility and Rigidity Analysis of HIV-1 gp120
The acquired-immunodeficiency syndrome (AIDS) has evolved into a major worldwide epidemic. Significant effort has been made in the development of antiviral therapies. A new strategy for vaccine and drug design that complements the existing cocktail therapy is to target entry of the human immunodeficiency virus (HIV). Such an approach provides the advantage of interfering with multiple intermediates in this multi-step process. Consequently, viral attachment, co-receptor binding, and viral-cell membrane fusion each provide promising targets for anti-AIDS drug discovery. The extraordinary conformational flexibility, glycosylation and strain variations complicate the development of an effective vaccine and cause general viral evasion of humoral immune response. Especially difficult to define are the conformation of gp120 prior to CD4 engagement as well as the relative orientations of the V1/V2 and V3 loops with respect to the inner and outer domains. In this study we used FIRST (Floppy Inclusion and Rigid Substructure Topography), a program based on graph theory, to analyze the flexibility and rigidity of all known HIV-1 gp120 structures. A flexibility index is used to describe and compare the spatial distribution of protein flexibility and rigidity of these structures in isolation and in complex with CD4, CD4-mimics and neutralizing antibodies. We observe a consistent drop in flexibility upon CD4 binding for a portion of the binding interface in different strains such as HxBc2 and Yu2 and less reduction for CD4 mimics. Using this flexibility analysis we identify a putative, consensus rigid core region with implications for vaccine design. Finally we present an exploration of the available conformational space sampled by the flexible regions of an unliganded gp120 structure which can provide insight for designing ligands that lock gp120 into a fusion inactive state.
Department of Physics, IUPUI