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.