Welcome to the Carey Group

Biophysical chemistry: Molecular origins of macromolecular affinity and specificity

The research in our laboratory is focused on understanding the molecular basis of interactions involving biological macromolecules. Molecular recognition is at the root of essentially all biological processes, and hence much of medicine. All cellular functions depend on protein-protein, protein-small molecule, protein-nucleic acid, or other intermolecular interactions. How do the correct partners identify each other against the background of numerous similar molecules present in the biological milieu? How are appropriate levels of affinity set? Our interest is centered on obtaining a detailed understanding of the underlying chemical and physical processes at work in these interactions. In doing so, we apply both structural and thermodynamic analysis in order to achieve an integrated picture.

All molecular interactions have characteristic values of affinity and specificity. Biology demands that each molecular interaction has a unique combination of affinity and specificity in order to serve its physiological purpose in the organism. It is commonly thought that affinity and specificity arise from favorable bonding interactions between partners that can be observed in structural analysis of complexes. However, many examples of biological interactions have an enthalpy change for complex formation that is near zero or even positive. This kind of result indicates that the net contribution from bonding interactions is not the principal driving force for complex formation. In some cases of this kind it has been shown that entropy changes arising from such cryptic sources as surface solvation can dominate the overall free energy change for complex formation. Thus, differences in solvation or other properties of two related molecules can lead to large differences in their affinities even when differences in their bonding interactions are minor. These and other cryptic contributions are, by definition, undetected by structural methods. Thus, there is no simple relationship between bonding (structure) and the strength or specificity of interaction, which may have unforeseen (and unseen) molecular origins.

We are currently working on several systems that exemplify different molecular mechanisms for achieving the values of affinity and specificity required to serve their biological purpose. In each system under study, our experimental approaches range from basic molecular biology such as cloning, through biochemistry including purification and characterization and quantitative analysis of binding equilibria, to biophysical methods including calorimetry and electronic and NMR spectroscopies. By comparing and contrasting the structural and thermodynamic features in several cases, we hope to distill out the generalities that are essential for understanding the basis of recognition. The general conclusions also have impact in related areas, including drug development.