Conformational Transition of the Mpro Enzyme: A Computational Approaches for Predicting Alternative Binding Sites of an Anti-COVID Molecule

Abstract

The Mpro enzyme has gained popularity as a target in the life cycle of COVID-19 for the  discovery of anti-COVID molecules. The current hypothesis focuses on seventy-two crystal  structures of Mpro, both in Conformation A (ConA) and Conformation AB (ConAB) forms.  However, no studies have yet evaluated the following aspects: (i) a comparative analysis of  ligand-bound crystal structures versus their ligand-free counterparts in both ConA and  ConAB forms; and (ii) the identification of alternative binding sites for anti-COVID molecules  within the crystal structure of Mpro. The native state is more dynamic than the ligand-bound  form, stabilizing after binding to the corresponding ligand. Moreover, Asn142 and Leu141 in  ConAB-native, Asn277 and Thr304 in ConAB ligand-bound, Phe305 and Asn72 in ConA  native and Ser46 and Glu47 in ConA ligand-bound structures are primarily flexible. During  the transition from native to ligand-bound form, Val73, Lys100, Ser123, Cys128, Lys137,  Cys156 and Phe294 residues have changed their structural position from buried to exposed in  the ConA and Leu50, Arg60, Asn214, Ala285 and Phe305 in the ConAB, respectively.  Similarly, Phe305 changed its structural conformation from exposure to burial in the ConA. Investigation on the multi-conformation analysis of 72 crystal structures highlighted that the  residues His41, Glu189, Asn142 and Arg188 (apart from His163, Glu166 and Gln189) might  act as a catalytic partner along with the Cys-His catalytic dyad and they may be considered  alternative binding site of the anti-COVID molecule of the Mpro enzyme.