Order Parameters and Conformational Entropies Derived from Combined NMR and Molecular Dynamics Approach

Conformational dynamics of proteins and other biomolecules are intimately tied to their function. Conformational fluctuations contribute to the conformational entropy, potentially making major contributions to the free energy of ligand binding and allostery. NMR relaxation stands out as a unique experimental technique capable of providing information on conformational entropy at atomic resolution, via order parameters measured for specific interaction tensors. On its own, NMR relaxation can provide information on the conformational entropy associated only with those specific degrees of freedom probed by the order parameters. By contrast, molecular dynamics simulations are capable in principle of providing the total conformational entropy, provided that the trajectories reach convergence with respect to this property. NMR relaxation data has long been used to validate molecular dynamics simulations. Thus, using a combination of NMR relaxation and molecular dynamics simulations, it is possible to achieve accurate estimates of the total conformational entropy in an experimentally validated approach. Recent advances in molecular dynamics simulation methodology and force-field development, sophisticated approaches for assessing the extent of high-order coupling among degrees of freedom, improved experimental characterization of order parameters across a wider range of time scales, and empirical relationships between order parameters and conformational entropy combine to put the challenging goal of obtaining a statistical thermodynamic view of the molecular contributions to binding affinity within reach in the near future. Keywords: relaxation; probability distribution; statistical thermodynamics; order parameter; configurational entropy; conformational entropy; molecular dynamics simulations