On the mechanisms of protein interactions: predicting their affinity from unbound tertiary structures.

Motivation: The characterization of the protein-protein association mechanisms is crucial to understanding how biological processes occur. It has been previously shown that the early formation of non-specific encounters enhances the realization of the stereospecific (i.e. native) complex by reducing the dimensionality of the search process. The association rate for the formation of such complex plays a crucial role in the cell biology and depends on how the partners diffuse to be close to each other. Predicting the binding free energy of proteins provides new opportunities tomodulate and control protein-protein interactions. However, existing methods require the 3D structure of the complex to predict its affinity, severely limiting their application to interactions with known structures. Results: We present a new approach that relies on the unbound protein structures and protein docking to predict protein-protein binding affinities. Through the study of the docking space (i.e. decoys), the method predicts the binding affinity of the query proteins when the actual structure of the complex itself is unknown. We tested our approach on a set of globular and soluble proteins of the newest affinity benchmark, obtaining accuracy values comparable to other state-of-art methods: a 0.4 correlation coefficient between the experimental and predicted values of Delta G and an error < 3Kcal/mol.