Exploration of Multi-State Conformational Dynamics and Underlying Global Functional Landscape of Maltose Binding Protein

An increasing number of biological machines have been revealed to have more than two macroscopic states. Quantifying the underlying multiple-basin functional landscape is essential for understanding their functions. However, the present models seem to be insufficient to describe such multiple-state systems. To meet this challenge, we have developed a coarse grained triple-basin structure-based model with implicit ligand. Based on our model, the constructed functional landscape is sufficiently sampled by the brute-force molecular dynamics simulation. We explored maltose-binding protein (MBP) which undergoes large-scale domain motion between open, apo-closed (partially closed) and holo-closed (fully closed) states responding to ligand binding. We revealed an underlying mechanism whereby major induced fit and minor population shift pathways co-exist by quantitative flux analysis. We found that the hinge regions play an important role in the functional dynamics as well as that increases in its flexibility promote population shifts. This finding provides a theoretical explanation of the mechanistic discrepancies in PBP protein family. We also found a functional “backtracking” behavior that favors conformational change. We further explored the underlying folding landscape in response to ligand binding. Consistent with earlier experimental findings, the presence of ligand increases the cooperativity and stability of MBP. This work provides the first study to explore the folding dynamics and functional dynamics under the same theoretical framework using our triple-basin functional model. Author Summary: A central goal of biology is to understand the function of the organism and its constituent parts at each of its scales of complexity. Function at the molecular level is often realized by changes in conformation. Unfortunately, experimental explorations of global motions critical for functional conformational changes are still challenging. In the present work, we developed a coarse grained triple-well structure-based model to explore the underlying functional landscape of maltose-binding protein (MBP). By quantitative flux analysis, we uncover the underlying mechanism by which the major induced fit and minor population shift pathways co-exist. Though we have previously lent credence to the assertion that dynamical equilibrium between open and minor closed conformations exist for all the free PBPs, the generality of this rule is still a matter of open debate. We found that the hinge flexibility is favorable to population shift mechanism. This finding provides a theoretical explanation of the mechanism discrepancies in PBP protein family. We also simulated the folding dynamics using this functional multi-basin model which successfully reproduced earlier protein melting experiment. This represents an exciting opportunity to characterize the interplay between folding and function, which is a long-standing question in the community. The theoretical approach employed in this study is general and can be applied to other systems.