Energy landscape of all-atom protein-protein interactions revealed by multiscale enhanced sampling.

Kei Moritsugu,Akinori Kidera,Tohru Terada,Alexander Mackerell

doi:10.1371/journal.pcbi.1003901

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.

Highlights

Protein-protein interactions are the fundamental components in the interaction networks describing cellular processes such as metabolic reactions and signal transduction
When trying to acquire a more detailed understanding of the association and dissociation processes of protein complexes, we encounter some complicated physics involved in these protein-protein interactions, in which a subtle balance between the weak atomic interactions and solvation determines the marginal stability/ affinity and the specificity [1,2,3]
There are two stages in the process involved in the formation of a protein complex, the ‘‘diffusion-collision’’ process from the fully separated states to the encounter complex, and the ‘‘association’’ process from the encounter complex to the native complex structure

Summary

Introduction

Protein-protein interactions are the fundamental components in the interaction networks describing cellular processes such as metabolic reactions and signal transduction. When trying to acquire a more detailed understanding of the association and dissociation processes of protein complexes, we encounter some complicated physics involved in these protein-protein interactions, in which a subtle balance between the weak atomic interactions and solvation determines the marginal stability/ affinity and the specificity [1,2,3] Such a physical picture is reminiscent of the complexity in protein folding, which has been overviewed from the energy landscape picture linking the unfolded states to the folded state [4,5]. The large scale configurational sampling by conventional equilibrium molecular dynamics (MD) simulations is a difficult task due to the slow kinetics and a large number of degrees of freedom in the sampling space To solve this problem more elaborate simulation techniques have been used to calculate the free energy surface (FES), such as steered MD [26], constrained MD [27], and the weighted histogram analysis method [28].

Methods

Results

Conclusion