REACTIVITY OF THE HIV-1 NUCLEOCAPSID PROTEIN P7 ZINC-FINGER DOMAINS FROM THE PERSPECTIVE OF DENSITY-FUNCTIONAL THEORY

The reaction of the human immunodeficiency virus type 1 (HIV-1) nucleo capsid protein p7 (NCp7) with a variety of electrophilic agents was in vestigated by experimental measurements of Trp(37) fluorescence decay and compared,vith theoretical measures of reactivity based on density- functional theory in the context of the hard and soft acids and bases principle, Statistically significant correlations were found between r ates of reaction and the ability of these agents to function as soft e lectrophiles. Notably, the molecular propel ty that correlated stronge st was the ratio of electronegativity to hardness, chi(2)/eta, a quant ity related to the capacity of an electrophile to promote a soft (cova lent) reaction. Electronic and steric determinants of the reaction wer e also probed by Fukui function and frontier-orbital overlap analysis in combination with protein-ligand docking methods. This analysis iden tified selective ligand docking regions within the conserved zinc fing er domains that promoted reaction. The Cys(49) thiolate was found over all to be the NCp7 site most susceptible to electrophilic attack.