How Intrinsic Dynamics Mediates the Allosteric Mechanism in the ABC Transporter Nucleotide Binding Domain Dimer.

A protein's architecture facilitates specific motions-intrinsic dynamic modes-that are employed to effect function. Here we used molecular dynamics (MD) simulations to investigate the dynamics of the MJ0796 ABC transporter nucleotide-binding domain (NBD). ABC transporter NBDs form a rotationally symmetric dimer whereby two equivalent active sites are formed at their interface; in complex with a dimer of transmembrane domains they hydrolyze ATP to energize translocation of substrates across cellular membranes. Our data suggest the ABC NBD's ensemble of functional states can be understood predominately in terms of conformational changes between its major subdomains, occurring along two orthogonal dynamic modes. The data show that ligands and oligomeric interactions modulate the equilibrium conformation of the NBD with respect to these motions, suggesting that allostery is achieved by affecting the energetic profile along these two modes. The observed dynamics and allostery integrate consonantly and logically within a mechanistic framework for the ABC NBD dimer, which is supported by a large body of experimental and theoretical data, providing a higher resolution view of the enzyme's dynamic cycle. Our study shows how valuable mechanistic inferences can be derived from accessible short-time scale MD simulations of an enzyme's substructures.