A NEW METHOD FOR THE INTERPRETATION OF DYNAMICS TRAJECTORIES IN THE CONFORMATIONAL-ANALYSIS OF HIV RECEPTOR MUTANTS

Several mutants of the CD4 receptor of the cell membrane surface prote in of the human T-lymphocytes were shown to have reduced binding poten tial for the gp120 envelope glycoprotein of human immunodeficiency vir us (HIV). Simultaneously, the loss of its original immunological activ ity, the ability to recognize the major histocompatibility complex cla ss II (MHC II) antigens, has also been observed. Only a single modific ation of the CD4, the Asn52Asp mutant, resulted in a noticeable functi onal separation of the two different activities: the loss of its gp120 binding and the preservation of its original MHC II immunological act ivity. Although a large variety of point mutants have been generated, no consistent model has been suggested which could offer an explanatio n or a structure-activity relationship of the CD4 receptor. In this pa per a generalized model is provided on the basis of selected, well est ablished, mutants. Of the numerous mutants, published in the literatur e, three were selected for the present study where two of them were mu tated at position 52 (Asn52Asp and Asn52Ala) and one at position 46 (L ys46Ala). The highest resolution X-ray geometry of the wild-type CD4 r eceptor has been used for the molecular dynamics (MD) simulations. The conformational behaviour of the wild-type and several of its mutants were investigated using an empirical force field (AMBER) both in terms of gradient geometry optimization and MD simulations. The global char acter of the backbone conformation was generally preserved during MD s imulations. By contrast, the 41-60 subunit of the Lys46Ala mutant show ed a significant modification. Trajectory analysis of MD simulations ( using 50 ps time intervals) of the wild-type CD4 and its three differe nt mutants were performed using a new type of trajectory interpretatio n. This involved the use of the amino acid conformation assignment of proteins (ACAP) software which has been developed by using ab initio-t ype calculations on model peptides, for the notation of the secondary structure. This method has been adapted as a convenient tool for the a nalysis of dynamical trajectories.