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.