Protein–Ligand Binding Molecular Details Revealed by Terahertz Optical Kerr Spectroscopy: A Simulation Study

[Image: see text] Picosecond fast motions and their involvement in the biochemical processes such as protein–ligand binding has engaged significant attention. Terahertz optical Kerr spectroscopy (OKE) has the superior potential to probe these fast motions directly. Application of OKE in protein–ligand binding study is, however, limited by the difficulty of quantitative atomistic interpretation, and the calculation of Kerr spectrum for entire solvated protein complex was considered not yet feasible, due to the lack of one consistent polarizable model for both configuration sampling and polarizability calculation. Here, we analyzed the biochemical relevance of OKE to the lysozyme–triacetylchitotriose binding based on the first OKE simulation using one consistent Drude polarizable model. An analytical multipole and induced dipole scheme was employed to calculate the off-diagonal Drude polarizability more efficiently and accurately. Further theoretical analysis revealed how the subtle twisting and stiffening of aromatic protein residues’ spatial arrangement as well as the confinement of small water clusters between ligand and protein cavity due to the ligand binding can be examined using Kerr spectroscopy. Comparison between the signals of bound complex and that of uncorrelated protein/ligand demonstrated that binding action alone has reflection in the OKE spectrum. Our study indicated OKE as a powerful terahertz probe for protein–ligand binding chemistry and dynamics.