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

Abstract

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.

SARS‐CoV‐2 main protease mutation analysis via a kinematic method

“…KFA is an efficient technique to assess functional macromolecular flexibility from static structures and to model conformational transitions. It can provide insights into how molecular functions are influenced by their flexibility 37,39–42 . For example, we previously showed and experimentally confirmed how abrogating a single hydrogen bond initiated a cascade of structural changes critical for catalysis in the enzyme isocyanide hydratase (ICH) 38 …”

“…It can provide insights into how molecular functions are influenced by their flexibility. 37,[39][40][41][42] For example, we previously showed and experimentally confirmed how abrogating a single hydrogen bond initiated a cascade of structural changes critical for catalysis in the enzyme isocyanide hydratase (ICH). 38 KFA represents molecules as articulated multi-body complexes with dihedral angles as revolute degrees of freedom, while non-covalent interactions such as hydrogen bonds and hydrophobic interaction are modeled as holonomic constraints.…”

“…We started with 112 Mpro crystal structures (see Chen et al 42 ) from the PDB. Then we performed simultaneous mutation and individually mutated each of these 47 sites.…”

Kinematic analysis of kinases and their oncogenic mutations – Kinases and their mutation kinematic analysis

“…The utilization of kinematic flexibility analysis (KFA) offers an efficient approach in examining the flexibility of functional macromolecules, even in static structures. This technique enables the modeling of conformational transitions, shedding light on the influence of molecular flexibility on their respective functions [42][43][44][45][46][47][48]. In a previous study, we demonstrated and experimentally validated the significance of disrupting a single hydrogen bond, triggering a sequence of structural alterations crucial for catalytic activity in the enzyme isocyanide hydratase (ICH) [49].…”