Molecular recognition—the non-covalent association of one molecule with another—is centrally important to biology. Non-covalent association guides the folding of proteins, the translation of DNA, the catalytic transformation of cellular metabolites, and the propagation of information throughout the cell (and between cells). The fundamental molecular driving forces involved in interactions between molecules have been enumerated (ionic, electrostatic, hydrophobic, etc.), but are not well understood. Building a fundamental understanding of these interactions will facilitate the rational design of biologically active molecules—from antibodies to ligands, which could serve as drug leads—, and enable the engineering of novel biologically-inspired, protein-based materials.
Our group studies molecular recognition in the contexts of protein-ligand interactions, protein crystallization, and multivalent receptor-ligand association. We integrate tools of calorimetry and thermodynamic analysis, protein crystallography and structural analysis, capillary electrophoresis, and molecular dynamics simulations with the goal of building structure-function relationships that will help us to understand the molecular-level origins that guide affinity and specificity in biomolecular association. We are particularly interested in the role water in hydrophobic interactions (1–4) and ionic interactions (5) (particularly those involving protein concavities), the relationship between protein surface chemistry and the interactions among proteins in their crystals, and the role of bivalency in biology and especially in the immune system (6, 7).
1. Snyder, P.W., Mecinovic.J., Moustakas.D.T., Thomas.S.W., Harder.M., Mack.E.T., Lockett.M.R., Heroux.A., Sherman.W., and Whitesides.G.M. (2011) "Mechanism of the hydrophobic effect in the biomolecular recognition of arylsulfonamides by carbonic anhydrase", Proc Natl Acad Sci 108:17889–17894.
2. Snyder PW, Lockett MR, Moustakas DT, Whitesides GM (2014) "Is it the shape of the cavity, or the shape of the water in the cavity?", Eur Phys J Spec Top 223(5):853–891.
3. Breiten, B., Lockett.M., Sherman.W., Fujita.S., Al-Sayah.M., Lange.H., Bowers.C.M., Heroux.A., Krilov.G., and Whitesides.G.M., (2013) "Water networks contribute to enthalpy/entropy compensation in protein-ligand binding", J Am Chem Soc 135:15579–15584.
4. Lockett, M., Lange.H., Breiten.B., Heroux.A., Sherman.W., Rappoport.D., Yau.P.O., Snyder.P.W., and Whitesides.G.M. (2013) "The binding of benzoarylsulfonamide ligands to human carbonic anhydrase is insensitive to formal fluorination of the ligand" Angew Chemie - Int Ed 125, 7868-7871.
5. Fox, J.M., Kang.K., Sherman.W., Heroux.A., Sastry.M., Baghbanzadeh.M., Lockett.M.R., and Whitesides.G.M., (2015) "Interactions between Hofmeister anions and the binding pocket of a protein", J Am Chem Soc 137(11):3859–3866.
6. Mack, E.T, Snyder.P.W., Perez-Castillejos.R., Bilgicer.B., Moustakas.D.T., Butte.M.J., and Whitesides.G.M. (2012) "Dependence of avidity on linker length for a bivalent ligand-bivalent receptor model system", J Am Chem Soc 134(1):333–345.
7. Mack, E.T., Snyder.P.W., Perez-Castillejos.R., and Whitesides.G.M. (2011) "Using covalent dimers of human carbonic anhydrase II to model bivalency in immunoglobulins", J Am Chem Soc 133(30):11701–11715.