Configurations of nickel-cyclam antiviral complexes and protein recognition

Nickel (II)-xylylbicyclam is a potent anti-HIV agent and binds strongly to the CXCR4 co-receptor. We have investigated configurational equilibria of Ni-II-cyclam derivatives, since these are important for receptor recognition. Crystallographic studies show that both trans and cis configurations are readily formed: [Ni(cyclam)-(OAc)(2)](H2O)-H-. adopts the trans-III configuration with axial monodentate acetates, as does [Ni(benzylcyclam)(NO3)(2)] with axial nitrate ligands, whereas [Ni(benzylcyclam)(OAc)](OAc)(.)2H(2)O has an unusual folded cis-V configuration with Ni-II coordination to bidentate acetate. UV/Vis and NMR studies show that the octahedral trans-III configuration slowly converts to square-planar trans-1 in aqueous solution. For Ni-II-xylylbicyclam, a mixture of cis-V and trans-I configurations was detected in solution. X-ray diffraction studies showed that crystals of lysozyme soaked in Ni-II-cyclam or Ni(II)2-xylylbicyclam contain two major binding sites, one involving Ni-II coordination to Asp101 and hydrophobic interactions between the cyclam ring and Trp62 and Trp63, and the second hydrophobic interactions with Trp123. For Ni-II-cyclam bound to Asp101, the cis-V configuration predominates.