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

Abstract

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.

Exploring Configuration Space and Path Space of Biomolecules Using Enhanced Sampling Techniques—Searching for Mechanism and Kinetics of Biomolecular Functions

“…(a) Larger molecular systems: Obviously, these enhanced sampling techinques will be used for much larger systems; recent focus of computational studies is on protein-protein, protein-DNA, protein-RNA, complexes, proteins in membrane, proteins in crowded environment, so the signaling pathways in a cell would be a next target [90] as already studied in [30,34]. Anton [6] is very promising, but it is still necessary to devise efficient numerical algorithms.…”

“…The temperature and mass of the CG model must then be set to satisfy the conditions of adiabatic separation and β /β → 0. To do this, e.g., the kinetic energies of the MM models need to be examined whether the energy flow from CG to MM is negligible [30,32].…”

“…The formation of barnase-barstar complex was simulated on atomic detail by use of MSES, demonstrating a funnel-like energy landscape of the strong binder (with high affinity) which is formed through the specific side-chain interactions and the desolvation (Fig. 1b) [30]. In contrast, the complex of di-ubiquitin (di-UB) and UB-binding domain (UBD) with relatively low affinity was found to have a subtle stability with an ensemble of highly dynamic structures, allowing dynamic recognition consisting of various binding modes [34].…”

“…In these methods, we exchange some parameters in the potential function such as force constants. These methods were further extended to multiscale systems using coupling between fine and coarse-grained DoF by Moritsugu, Terada, and Kidera [27][28][29][30][31][32][33][34][35] as described below. (This method is also considered as an extension of resolution replica exchange [36].…”

“…We will introduce this method and discuss some applications to molecular systems below. [29,31] and applied them to many protein systems of biological importance [28,30,[32][33][34] as described below.…”