Research: Intermolecular Interactions

Intermolecular interactions govern liquid structure, solvation energies, crystal structures, adsorption of gases onto surfaces, and the binding of drug molecules to protein pockets. They are of foundational importance for crystal engineering and rational drug design. Despite this, they are still only incompletely understood. Moreover, many "standard" computational chemistry methods give unreliable results for intermolecular interactions. Thus, their computational modeling remains a frontier area of modern quantum chemistry.

We are developing improved theoretical methods and software for intermolecular interactions, and using these tools to study the fundamental forces of intermolecular interactions in important prototype molecular systems (including π-π, CH/π, SH/π, etc., interactions) to determine their strength, geometric dependence, and substituent effets. These studies are providing insight into how intermolecular interactions work in the context of more complex systems. Our research demonstrated that London dispersion forces, often ignored or assumed relatively unimportant, can play a key role in how substituents affect the strength of π-π interactions (at odds with previous conventional wisdom in the field, including the "Hunter-Sanders" rules). Our work also overturned previous experimental estimates for the binding energy of the gas-phase benzene dimer. Another key finding is that π-π interactions in DNA feature very significant contributions from orbital-orbital overlap ("charge penetration"). Such interactions are completely ignored in standard molecular dynamics simulations, and the stability of DNA and RNA in such simulations is thus due to large error cancellations amongst other terms in those models.

We are also studying intermolecular interactions in the context of aqueous solvent, protein-ligand interactions, and the lattice energies of molecular crystals. Our study of ligands binding to the factor Xa protein demonstrated that changing substituents in the ligand can lead to complicated changes in the binding energy, driven by changes in the interactions between the drug's dipole moment and the peptide bond dipoles in the protein. Another study demonstrated that π-π interactions are not greatly changed when aromatic molecules are moved from the gas phase to an aqueous solution; water molecules of course compete with an aromatic molecule for the opportunity to interact with another aromatic molecule, but the physics of the direct interaction between the aromatic solute molecules themselves is essentially as it is in the gas phase.

Representative Publications:

  • “High-Order Quantum-Mechanical Analysis of Hydrogen Bonding in Hachimoji and Natural DNA Base Pairs,” R. L. Kumawat and C. D. Sherrill, J. Chem. Inf. Model. 63, 3150-3157 (2023) (doi: 10.1021/acs.jcim.3c00428)
  • “The Influence of a Solvent Environment On Direct Non-Covalent Interactions Between Two Molecules: A Symmetry-Adapted Perturbation Theory Study of Polarization Tuning of π-π Interactions by Water,'' D. A. Sirianni, X. Zhu, D. F. Sitkoff, D. L. Cheney, and C. D. Sherrill, J. Chem. Phys. 156, 194306 (2022) (doi: 10.1063/5.0087302)
  • “Tuning DNA Supramolecular Polymers by Addition of Small, Functionalized Nucleobase Mimics", C. Lachance-Brais, C. Hennecker, A. Alenaizan, X. Luo, V. Toader, M. Taing, C. D. Sherrill, A. Mittermaier, and H. Sleiman, J. Am. Chem. Soc. 143, 19824-19833 (2021). (doi: 10.1021/jacs.1c08972)
  • “Noncovalent Helicene Structure between Nucleic Acids and Cyanuric Acid,” A. Alenaizan, K. Fauche, R. Krishnamurthy, and C. D. Sherrill, Chem. Eur. J. 27, 4043-4052 (2021). (doi: 10.1002/chem.202004390)
  • “Tipping the Balance between S-π and O-π Interactions,” J. Hwang, P. Li, M. D. Smith, C. E. Warden, D. A. Sirianni, E. C. Vik, J. M. Maier, C. J. Yehl, C. D. Sherrill, and K. D. Shimizu, J. Am. Chem. Soc. 140, 13301-13307 (2018). (doi: 10.1021/jacs.8b07617)
  • “The Surprising Importance of Peptide Bond Contacts in Drug-Protein Interactions,” R. M. Parrish, D. F. Sitkoff, D. L. Cheney, and C. D. Sherrill, Chem. Eur. J. 23, 7887-7890 (2017). (doi: 10.1002/chem.201701031)
  • “Analysis of Transition State Stabilization by Non-Covalent Interactions in the Houk-List Model of Organocatalyzed Intermolecular Aldol Additions using Functional-Group Symmetry-Adapted Perturbation Theory,” B. W. Bakr and C. D. Sherrill, Phys. Chem. Chem. Phys. 18, 10297-10308 (2016). (doi: 10.1039/c5cp07281f)
  • “Assessment of Empirical Models versus High-Accuracy Ab Initio Methods for Nucleobase Stacking: Evaluating the Importance of Charge Penetration,” T. M. Parker and C. D. Sherrill, J. Chem. Theory Comput. 11, 4197-4202 (2015). (doi: 10.1021/acs.jctc.5b00588)
  • “Quantum Mechanical Evaluation of π-π vs. Substituent-π Interactions in π-Stacking: Direct Evidence for the Wheeler-Houk Picture,” R. M. Parrish and C. D. Sherrill, J. Am. Chem. Soc. 136, 17386-17389 (2014). (doi: 10.1021/ja5101245)
  • “Energy Component Analysis of π Interactions,” C. D. Sherrill, Acc. Chem. Res. 46, 1020-1028 (2013). (doi: 10.1021/ar3001124)
  • “Quantum Mechanical Analysis of the Energetic Contributions to π Stacking in Nucleic Acids versus Rise, Twist, and Slide,” T. M. Parker, E. G. Hohenstein, R. M. Parrish, N. V. Hud, and C. D. Sherrill, J. Am. Chem. Soc. 135, 1306-1316 (2013). (doi: 10.1021/ja3063309)