Energy Landscape of All-Atom Protein-Protein Interactions Revealed by Multiscale Enhanced Sampling

Protein-protein interactions are regulated by a subtle balance of complicated atomic interactions and solvation at the interface. To understand such an elusive phenomenon, it is necessary to thoroughly survey the large configurational space from the stable complex structure to the dissociated states using the all-atom model in explicit solvent and to delineate the energy landscape of protein-protein interactions. In this study, we carried out a multiscale enhanced sampling (MSES) simulation of the formation of a barnase-barstar complex, which is a protein complex characterized by an extraordinary tight and fast binding, to determine the energy landscape of atomistic protein-protein interactions. The MSES adopts a multicopy and multiscale scheme to enable for the enhanced sampling of the all-atom model of large proteins including explicit solvent. During the 100-ns MSES simulation of the barnase-barstar system, we observed the association-dissociation processes of the atomistic protein complex in solution several times, which contained not only the native complex structure but also fully non-native configurations. The sampled distributions suggest that a large variety of non-native states went downhill to the stable complex structure, like a fast folding on a funnel-like potential. This funnel landscape is attributed to dominant configurations in the early stage of the association process characterized by near-native orientations, which will accelerate the native inter-molecular interactions. These configurations are guided mostly by the shape complementarity between barnase and barstar, and lead to the fast formation of the final complex structure along the downhill energy landscape.Author Summary: Dynamic nature of the protein-protein interactions is an important element of cellular processes such as metabolic reactions and signal transduction, but its atomistic details are still unclear. Computational survey using molecular dynamics simulation is a straightforward method to elucidate these atomistic protein-protein interaction processes. However, a sufficient configurational sampling of the large system containing the atomistic protein complex model and explicit solvent remains a great challenge due to the long timescale involved. Here, we demonstrate that the multiscale enhanced sampling (MSES) successfully captured the atomistic details of the association/dissociation processes of a barnase-barstar complex covering the sampled space from the native complex structure to fully non-native configurations. The landscape derived from the simulation indicates that the association process is funnel-like downhill, analogously to the funnel landscape of fast-folding proteins. The funnel was found to be originated from near-native orientations guided by the shape complementarity between barnase and barstar, accelerating the formation of native inter-molecular interactions to complete the final complex structure.