Biology Department Seminar

The study of associations between two bio-molecules is the key to Understanding molecular recognition and function. Molecular function is often thought to be determined by underlying structures. Here, combining a single molecule study of protein binding with an energy-landscape-inspired microscopic model, we found strong evidence that bio-molecular recognition is determined by flexibilities in addition to structures. 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 and significant binding of CBD to Cdc42, and another with native folding of CBD and native binding of CBD to Cdc42. This shows that the binding process proceeds with a significant interface binding of CBD with Cdc42 first, without a complete folding of CBD, and that binding and folding are then coupled to reach the native binding state. 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 quantitatively in the model 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.