Presents the Friday Keck Center Teleconference*
Quantifying Specificity and Flexibility of Biomolecular Recognition
Jin Wang, Ph.D.,
Assistant Professor, Chemistry and Physics, SUNY Stony Brook
4:00 pm Friday
April 11th , 2008
5.521 Levin Hall
(Refreshments at 3:45)
Abstract: Affinity and specificity are two key ingredients for biomolecular recognition. While great progresses have been made towards quantifying affinity, specificity is less addressed. We carried the investigation of a novel description of specificity in enzyme-ligand binding based on energy landscape theory. We define intrinsic specificity (ISR), which describes the level of discrimination of the minimum energy protein-ligand complex from the weaker binding states of the same ligand. We discuss the relationship between the intrinsic specificity and the conventional definition of specificity. In a binding study of 1000 molecules selected from an NCI database with the enzyme COX-2, we demonstrate a direct correlation between ISR value and structural match of small molecules with COX-2. We further observe that the known selective inhibitors of COX-2 all have high ISR values while nonselective COX inhibitors have lower ISR values. We suggest that intrinsic specificity ratio may be a useful criterion and a complement to affinity in initial drug screening and in searching for potential drug lead compounds.
Molecular function is often thought to be determined by underlying structures. Here, combining a single-molecule study of protein binding with an energy-landscape\u2013inspired microscopic model, we found strong evidence that biomolecular recognition is determined by flexibilities in addition to structures in signaling protein-protein recognition of CDC42 with CBD portion of WASP. With our model, the underlying free-energy landscape of the binding can be explored. There are two distinct conformational states at the free-energy minimum, one with partial folding of CBD itself and significant interface binding of CBD to Cdc42, and the other with native folding of CBD itself and native interface binding of CBD to Cdc42. This shows that the binding process proceeds as first binding of CBD to CDC42 and then folding. The single-molecule experimental finding of dynamic fluctuations among the loosely and closely bound conformational states can be identified with the theoretical, calculated free-energy minimum and explained as a result of binding associated with large conformational changes. The theoretical predictions identified certain key residues for binding that were consistent with mutational experiments. The combined study identified fundamental mechanisms and provided insights about designing and further exploring biomolecular recognition with large conformational changes. ( http://www.sunysb.edu/chemistry/faculty/jwang.htm )
