title: Characterization of the conformational state and flexibility of HIV-1 glycoprotein gp120 core domain.
abstract: 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 beta strands 2 and 3 of the bridging sheet were very mobile and partially unfolded, and the organization among the inner and outer domains and beta 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.
authors.affiliation: Basic Research Program, Science Applications International Corporation-Frederick, Inc., Laboratory of Experimental and Computational Biology, NCI-Frederick, National Institutes of Health, Frederick, Maryland 21702, USA.
authors.forename: Yongping
authors.initials: Y
authors.lastname: Pan
authors.forename: Buyong
authors.initials: B
authors.lastname: Ma
authors.forename: Ozlem
authors.initials: O
authors.lastname: Keskin
authors.forename: Ruth
authors.initials: R
authors.lastname: Nussinov
mesh_terms: D020816:Amino Acid Motifs; D001665:Binding Sites; D015704:CD4 Antigens / Q000737:chemistry; D003198:Computer Simulation; D018360:Crystallography, X-Ray; D004252:DNA Mutational Analysis; D019277:Entropy; D015699:HIV Envelope Protein gp120 / Q000737:chemistry*; D007700:Kinetics; D008958:Models, Molecular; D009154:Mutation; D011485:Protein Binding; D011487:Protein Conformation; D017510:Protein Folding; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D012984:Software; D013816:Thermodynamics; D013997:Time Factors
chemical_list: D015704:CD4 Antigens; D015699:HIV Envelope Protein gp120