Kinematic Vibrational Entropy Assessment and Analysis of SARS CoV‑2 Main Protease

The three-dimensional conformations of a protein influence its function and select for the ligands it can interact with. The total free energy change during protein–ligand complex formation includes enthalphic and entropic components, which together report on the binding affinity and conformational states of the complex. However, determining the entropic contribution is computationally burdensome. Here, we apply kinematic flexibility analysis (KFA) to efficiently estimate vibrational frequencies from static protein and protein–ligand structures. The vibrational frequencies, in turn, determine the vibrational entropies of the structures and their complexes. Our estimates of the vibrational entropy change caused by ligand binding compare favorably to values obtained from a dynamic Normal Mode Analysis (NMA). Higher correlation factors can be achieved by increasing the distance cutoff in the potential energy model. Furthermore, we apply our new method to analyze the entropy changes of the SARS CoV-2 main protease when binding with different ligand inhibitors, which is relevant for the design of potential drugs.