Steven E. Wheeler

Postdoc: Houk Group

Current Research Interests (Houk group, UCLA)

My research involves applications of ab initio electronic structure theory and density functional theory (DFT) to problems in organic chemistry and molecular biology. The primary focus is on understanding non-covalent interactions operative in biochemical systems. This builds on expertise developed while a graduate student in the Schaefer group (2002-2006) at the Center for Computational Quantum Chemistry (CCQC). Projects carried out while at the CCQC are described under Previous Research.

Substituent Effects in Non-Covalent Interactions with Aromatic Rings (π-stacking, cation/π, CH/π, etc.)

Prevailing models of substituents effects in the sandwich configuration of the benzene dimer hinge upon the polarization of the π-electron cloud of the substituted ring. It is generally assumed that electron-withdrawing substituents enhance binding in the benzene dimer by withdrawing electron density from the π-cloud of the substituted ring, reducing the repulsive electrostatic interaction with the nonsubstituted benzene. Conversely, electron-donating substituents diminish the π-stacking interaction by donating excess electrons into the π-system. Based on computed interaction energies for a series of model systems, we have shown that π-polarization has not net effect on substituents effects. Instead, substituent effects in the benzene dimer arise from direct through-space interactions of the substituents with the unsubstituted ring. These through-space effects are both electrostatic and dispersive in nature.

A Similarly, in prototypical interaction between cations and substituted benzenes (e.g.: Na⁺•••C₆H₅X dimers), the variation in binding energies arises primarily from direct interactions between the substituent and the cation; effects of π-polarization are minor. This is also reflected in the behavior of electrostatic potentials surrounding substitueted aromatic rings. Contrary to popular assumptions, changes in the ESP above the center of substituted aromatic rings does not necessarily reflect changes in the aryl π-density, but is mostly due to through-space electrostatic effects of the substitutents.

For more information, see:

• "Substituent Effects in the Benzene Dimer are Due to Direct Interactions of the Substituents with the Unsubstituted Benzene", S. E. Wheeler and K. N. Houk, J. Am. Chem. Soc. 130, 10854 (2008).
• "Substituent Effects in Cation/π Interactions and Electrostatic Potentials above the Centers of Substituted Benzenes Are Due Primarily to Through-Space Effects of the Substituents", S. E. Wheeler and K. N. Houk, J. Am. Chem. Soc. 131, 3126 (2009).
• "Through-Space Effects of Substituents Dominate Molecular Electrostatic Potentials of Substituted Arenes", S. E. Wheeler and K. N. Houk, J. Chem. Theory Comput. 5, 2301 (2009).

Polycyclic aromatic hydrocarbons (PAHs) are carcinogenic components of soot and tobacco smoke. One PAH in particular, benzo[a]pyrene, is metabolized into a highly mutagenic polycyclic aromatic diol epoxide, (+)-BaP DE-2. This diol epoxide intercalates into DNA and them forms covalent adducts with both guanine and adenine nucleic acid bases. We are studing the non-covalent interactions between (+)-BaP DE-2 and the guanine-cytosine and adenine-thymine base pairs as a simple model for DNA intercalation.

Lupus is a debilitating autoimmune disease affecting perhaps a million people (mostly women) in the U.S. A hallmark of the disease is the presence of antibodies that bind single and double-stranded DNA. We are using computational chemistry to study the binding of single-stranded DNA by these anti-DNA antibodies. This binding occurs via a combination of π-stacking and hydrogen bonding interactions.