NbIT - A New Information Theory-Based Analysis of Allosteric Mechanisms Reveals Residues that Underlie Function in the Leucine Transporter LeuT

Complex networks of interacting residues and microdomains in the structures of biomolecular systems underlie the reliable propagation of information from an input signal, such as the concentration of a ligand, to sites that generate the appropriate output signal, such as enzymatic activity. This information transduction often carries the signal across relatively large distances at the molecular scale in a form of allostery that is essential for the physiological functions performed by biomolecules. While allosteric behaviors have been documented from experiments and computation, the mechanism of this form of allostery proved difficult to identify at the molecular level. Here, we introduce a novel analysis framework, called N-body Information Theory (NbIT) analysis, which is based on information theory and uses measures of configurational entropy in a biomolecular system to identify microdomains and individual residues that act as (i)-channels for long-distance information sharing between functional sites, and (ii)-coordinators that organize dynamics within functional sites. Application of the new method to molecular dynamics (MD) trajectories of the occluded state of the bacterial leucine transporter LeuT identifies a channel of allosteric coupling between the functionally important intracellular gate and the substrate binding sites known to modulate it. NbIT analysis is shown also to differentiate residues involved primarily in stabilizing the functional sites, from those that contribute to allosteric couplings between sites. NbIT analysis of MD data thus reveals rigorous mechanistic elements of allostery underlying the dynamics of biomolecular systems.Author Summary: We developed the new information theory-based analysis framework presented here, NbIT analysis, for the study of allosteric mechanisms in biomolecular systems from Molecular Dynamics trajectories. The illustrative application of NbIT to the analysis of the occluded state in the bacterial transporter LeuT, produced a quantitative representation of the allosteric behavior, and identified intramolecular channels that enable the long-distance information transmission. Our findings, identifying the roles of specific residues in the communication of the allosteric information, were validated by the recognition of residues that have been previously shown to play functional roles in this very well studied system. In addition, we show that application of NbIT analysis leads to the discrimination of functional roles by differentiating between residues that are essential to the dynamics within functional sites (e.g., the substrate binding sites), and residues whose role is to communicate between such functional sites. These results demonstrate that the information theoretical analysis presented here is a powerful tool for quantifying complex allosteric behavior in biomolecular systems and for identifying the crucial components underlying those behaviors.