Entropy localization in proteins.

The configurational entropy of a protein is under physiological conditions a major contributor to the free energy. Its quantitative characterization is therefore an important step toward the understanding of protein function. The configurational entropy of the oncoprotein MDM2, whose determination is a challenge by experiment alone, is studied here by means of 0.4 μs molecular dynamics computer simulations in both the presence and absence of the p53-peptide ligand. By characterizing protein motions in dihedral angle space, it is found that the motional amplitudes change considerably upon ligand binding while correlations between dihedral angle motions are remarkably well conserved. This applies for backbone and side-chain dihedral angle pairs at both short- and long-range distance to the binding site. As a direct consequence, the change of the configurational entropy can be decomposed into a sum of local contributions. This significantly facilitates the understanding of the relationship between protein dynamics and thermodynamics, which is important, for example, in the context of protein-ligand and protein-protein interactions. The findings also have implications for the direct derivation of entropy changes from site-specific dynamics measurements as afforded by NMR spectroscopy.