NORMAL-MODE ANALYSIS SUGGESTS IMPORTANT FLEXIBILITY BETWEEN THE 2 N-TERMINAL DOMAINS OF CD4 AND SUPPORTS THE HYPOTHESIS OF A CONFORMATIONALCHANGE IN CD4 UPON HIV BINDING

Human CD4 is the receptor for human immunodeficiency virus (HIV). It i s well established that the first domain of CD4 binds with high affini ty to gp120, an envelope protein of HIV, but it has also been demonstr ated that amino acids located in its second domain, within or close to residues 120-127 or 163-166 (lying 15 Angstrom away from the binding site), play a role in virus infectivity. We show here that these two s tretches of amino acids happen to be important for the largest amplitu de motion obtained with the normal-mode theory for the two N-terminal domains of human CD4: an overall rigid-body displacement of one domain with respect to the other. Such a 'hinge-bending' motion is unexpecte d since these two domains were found by crystallographers to be tightl y abutting, On the other hand, since for several proteins the hinge-be nding motion experimentally observed upon ligand binding was found to be similar to the largest amplitude motion obtained with the normal-mo de theory for these proteins, our results suggest that CD4 may undergo such a kind of conformational change upon HIV binding.