title: Molecular mechanism of HIV-1 gp120 mutations that reduce CD4 binding affinity.
abstract: The interaction of the HIV-1 fusion protein gp120 with its cellular receptor CD4 represents a crucial step of the viral infection process, thus rendering gp120 a promising target for the intervention with anti-HIV drugs. Naturally occurring mutations of gp120, however, can decrease its affinity for anti-infective ligands like therapeutic antibodies or soluble CD4. To understand this phenomenon on a structural level, we performed molecular dynamics simulations of two gp120 variants (termed gp1203-2 and gp1202-1), which exhibit a significantly decreased binding of soluble CD4. In both variants, the exchange of a nonpolar residue by glutamate was identified as an important determinant for reduced binding. However, those glutamates are located at different sequence positions and affect different steps of the recognition process: E471 in gp1203-2 predominantly affects the CD4-bound conformation, whereas E372 in gp1202-1 mainly modulates the conformational sampling of free gp120. Despite these differences, there exists an interesting similarity between the two variants: both glutamates exert their function by modulating the conformation and interactions of glycine-rich motifs (G366-G367, G471-G473) resulting in an accumulation of binding incompetent gp120 conformations or a loss of intermolecular gp120-CD4 hydrogen bonds. Thus, the present data suggests that interference with the structure and dynamics of glycine-rich stretches might represent a more widespread mechanism, by which gp120 mutations reduce binding affinity. This knowledge should be helpful to predict the resistance of novel gp120 mutations or to design gp120-ligands with improved binding properties. An animated interactive 3D complement (I3DC) is available in Proteopedia at http://proteopedia.org/w/Journal:JBSD:41.
authors.affiliation: a Bioinformatics , Institute for Biochemistry, Friedrich-Alexander-Universität Erlangen-Nürnberg , Fahrstrasse 17 , Erlangen , 91054 , Germany .
authors.forename: Kristin
authors.initials: K
authors.lastname: Kassler
authors.forename: Heinrich
authors.initials: H
authors.lastname: Sticht
mesh_terms: D001665:Binding Sites; D015704:CD4 Antigens / Q000737:chemistry*; D015699:HIV Envelope Protein gp120 / Q000737:chemistry / Q000235:genetics*; D015497:HIV-1 / Q000378:metabolism*; D006801:Humans; D056004:Molecular Dynamics Simulation; D009154:Mutation; D011487:Protein Conformation
chemical_list: D015704:CD4 Antigens; D015699:HIV Envelope Protein gp120