Density Functional Theory Modeling of It-Stacking and Electrophilic Donor-Acceptor Interactions with Application to Therapeutic Targeting of Zinc-Finger Proteins

Several viruses, including viruses that cause cancer, contain conserved zinc finger (ZF) proteins that are essential for viral reproduction, making them attractive drug targets for cancer and viral treatment. ZFs are small protein domains that have Zn2+ tetrahedrally coordinated to at least 2 Cys and His. They form three classes of ZFs depending on the amino acid ligands, CCHH, CCCH, and CCCC. Zn2+ is stable towards redox reactions; however, the Cys thiolates are redox active. Oxidation of the Cys thiolates release Zn2+, and the ZF loses its tertiary structure and can no longer bind DNA or RNA. Understanding the interaction of reducible sulfur and selenium compounds (rS/Se) with ZF proteins is valuable for explaining the beneficial chemoprevention, viruscidal activity and toxicity of these compounds and can guide the production of new chemopreventives and anti-viral agents. DFT was used to investigate the interaction of small r-S/Se compounds with models of three classes of ZF proteins. Density functional theory (DFT) calculations show that increasing the number of thiolate ligands coordinated to Zn2+ leads to stronger interactions with r-Se compounds due to the increase in the energy of the ZF HOMO. A high correlation was found between the LUMO energy of the r-S/Se compound the interaction energy, suggesting that the LUMO energy of a potential drug could be used to test its ability to oxidize a ZF protein. The nucleocapsid protein (NCp7) from the HIV-1 virus is an attractive drug target. Electrophilic compounds can inhibit NCp7 functions, but their lack of specificity has impeded their use as antiviral drugs. Because W37 of NCp7 π-stacks to Gua in the NCp7DNA binding site, compounds that bind with a higher affinity will be able to specifically inhibit NCp7 binding to DNA. Methylation or metalation is proposed to increase the stacking interaction between the positively charged base and W37 by lowering the LUMO of the base and bring it closer in energy to the HOMO of W. Small models of methylated and metalated Gua π-stacked to W were investigated with DFT. The interaction energies correlated with experimental Kπ values, and with the LUMO energy of the modified MeGua, suggesting that LUMO energies could give a quick estimation of it-stacking energy. For a more complete understanding of π-stacking interactions, a DFT study of dimers of small aromatic compounds was undertaken. Although dispersion and electrostatics are known to stabilize it-stacking interactions, the preference for parallel displaced (PD) and or twisted (TW) conformations over sandwich (S) geometries in these dimers is not well understood. Orbital analysis showed that PD or TW structures convert one or more π-type dimer MO with out-of-phase or antibonding inter-ring character at the S to in-phase or binding at the PD/TW structure. The change in dimer MO character was described by stack bond order (SBO), a term introduced as an analogy to the bond order in molecular orbital theory. The SBO of a S structure is zero; parallel displacement or twisting result in a non-zero SBO and overall bonding character. The total inter-ring Wiberg bond indices or total Ldwdin bond order, which quantify orbital interactions, is maximized at the optimal PD and or TW geometry. As a follow-up study, we investigated using SBO to formulate general principles that could be used to rationalize the preferred geometries of a broad range of it-stacking interactions. The ability to qualitatively predict the preferred geometry of it-stacked dimers using SBO would be beneficial to researchers that study the many systems that involve π-stacking interactions