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) nucleocapsid protein p7 (NCp7) with a variety of electrophilic agents was investigated by experimental measurements of Trp 37 fluorescence decay and compared with 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 rates of reaction and the ability of these agents to function as soft electrophiles. Notably, the molecular property that correlated strongest was the ratio of electronegativity to hardness, χ 2 /η, a quantity related to the capacity of an electrophile to promote a soft (covalent) reaction. Electronic and steric determinants of the reaction were also probed by Fukui function and frontier-orbital overlap analysis in combination with protein–ligand docking methods. This analysis identified selective ligand docking regions within the conserved zinc finger domains that promoted reaction. The Cys 49 thiolate was found overall to be the NCp7 site most susceptible to electrophilic attack.