A coarse-grained view of protein-protein recognition

One of the most important characteristics of proteins is their ability to specifically interact with other proteins and with other types of molecules to build supramolecular assemblies in order to perform different kinds of functions. Protein-protein interaction has been a subject of study in several sciences including biochemistry, structural biology, and computational biophysics/biology. One limitation that delays our understanding of molecular recognition is the lack of high-resolution three-dimensional structures of the protein-protein complexes. Because of this, the methods for computational prediction have gained popularity and importance but in many cases, the predicted complex is not accurate. Predicting the native three-dimensional conformation of protein-protein complexes still remains a big challenge.;Most biological processes in the cell involve a huge number of atoms and happen at time-scales that are frequently beyond the current limits of classical atomistic simulations. The ELNEDIN approach is a new and powerful coarse-grained representation with the ability to overcome size and time limits without deforming the overall shape of a protein. Previous studies have shown that the quality of the ELNEDIN scaffold influences the ability of the modeled proteins to experience structural transitions and to associate and form a stable complex.;The main objective of this thesis is to test if the ELNEDIN approach is able to discriminate native interfaces from non-native. The Barnase/Barstar complex, the RNase/Barnase complex and the Ubiquitin/Ubiquitin ligase complex were chosen to test this hypothesis. Each individual protein model was simulated using the ELNEDIN approach and the potential of mean force for the dissociation of the complex was calculated. Our results show: 1) It is possible to obtain accurate energy-profiles using the ELNEDIN approach. 2) The shape of the free energy landscape around a protein receptor has a funnel-like shape where the bottom of the funnel is the global minimum and it starts to increase smoothly. 3) The solvent plays an important role in the shape of the free energy profile. 4) The ELNEDIN approach is able to recognize the native conformation for hydrophilic interfaces. To further support the last result, an additional complex was chosen: the Nuclease A/Nuclease inhibitor A complex.