Response of Terahertz Protein Vibrations to Ligand Binding: Calmodulin-Peptide Complexes as a Case Study.

Terahertz vibrations are sensitive reporters of the structure and interactions of proteins. Ligand binding alters the nature and distribution of these collective vibrations. The ligand-induced changes in the terahertz protein vibrations contribute to the binding entropy and to the overall thermodynamic stability of the resultant protein-ligand complexes. Here, we have examined the response of the low-frequency (below 6 terahertz) collective vibrations of the calcium-loaded calmodulin (CaM) to binding to five different ligands, both in the presence and absence of water, using normal-mode analysis and molecular dynamics simulations. A comparison of the vibrational spectra of hydrated and dry systems reveals that protein-solvent interactions stiffen the terahertz protein vibrations and that these solvent-coupled collective vibrations contribute significantly to the hydration-sensitive variation in the vibrational entropy of CaM. In the absence of water, the low-frequency vibrations of CaM are stiffened by ligand binding. On the contrary, the number and the cumulative vibrational entropy of low-frequency vibrational modes (ω < 200 cm) of the hydrated CaM are increased noticeably after binding to the peptides, indicating binding-induced softening of collective vibrations of the protein. Although the calculated and experimental binding affinities of the chosen complexes correlated reasonably well, no systematic correlation was observed between the protein vibrational entropy and the binding affinity. The results underscored the importance of the interplay of protein-ligand and solvent interactions in modulating the low-frequency vibrations of proteins.