SUGGESTED BINDING MECHANISM OF THE HIV-GP120 TO ITS CD4 RECEPTOR

The molecular recognition and attachment of the CD4 molecule and the H IV envelope glycoprotein (gp120) might be described as a consecutive t hree-step molecular recognition process. (a) Long range interaction: e lectrostatic pre-orientation, (b) short range interaction: electronic attachment followed by a 'Locking-in' (via aromatic ring orientation) and (c) internal interaction (induced fit): conformational readjustmen t of the protein molecules. On the basis of the preliminary investigat ions (X-ray structures of CD4 and biological studies of CD4 and gp120 point mutants) we described a computational model. This approach consi sts of empirical calculations as well as ab initio level of quantum ch emistry. The conformational analysis of the wild type and mutant CD4 m olecules was supported by molecular mechanics and dynamics (Amber forc e field). The latter analysis involves the application of a novel meth od, the Amino Acid Conformation Assignment of Proteins (ACAP) software , developed for the notation of secondary protein structures. Accordin g to the cardinal role of the electrostatic factors during this intera ction, several ab initio investigations were performed for better unde rstanding of the recognition process on submolecular level. Using the above mentioned computational model, we could interpret the basic beha viours and predict some additional features of CD4-gp120 interaction, in spite of the missing gp120 X-ray structure.