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The main protease (Mpro) is essential for the replication of SARSCoV- 2, making it one of the major therapeutic targets for COVID-19 treatment. Here, we explored the conformational dynamics and energetics of the catalytic residue His41 in Mpro, as revealed by a rare conformational shift observed in the cocrystal structures of Mpro bound by certain inhibitors. Using steered molecular dynamics combined with umbrella sampling, we demonstrated that π−cation interactions between these inhibitors and the ionized catalytic dyad significantly reduced the energy barrier for the conformational flip of the His41 side chain. To further investigate the structure−activity relationship linked to this conformational change, we designed and synthesized a series of covalent inhibitors that control His41 flipping. Among these, compound H102-7 exhibited remarkable inhibitory activity with an IC50 of 5 nM. Drug resistance studies revealed that these inhibitors displayed improved resistance profiles compared to the clinically approved Mpro covalent inhibitor, Nirmatrelvir. This study integrates computational simulations, medicinal chemistry, and molecular biology to uncover an interesting allosteric effect of a key catalytic residue of SARS-CoV-2 Mpro and yields new promising molecules for the further development of Mpro-targeted therapeutic intervention. 

This paper reports the fabrication of β-Ga 2 O 3 nanomembrane (NM) based flexible photodetectors (PDs) and the investigation of their optoelectrical properties under bending conditions. Flexible β-Ga 2 O 3 NM PDs exhibited reliable solar-blind photo-detection under bending conditions. Interestingly, a slight shifting in wavelength of the maximum solar-blind photo-current was observed under the bending condition. To investigate the reason for this peak shifting, the optical properties of β-Ga 2 O 3 NMs under different strain conditions were measured, which revealed changes in the refractive index, extinction coefficient and bandgap of strained β-Ga 2 O 3 NMs due to the presence of nano-sized cracks in the β-Ga 2 O 3 NMs. The results of a multiphysics simulation and a density-functional theory calculation for strained β-Ga 2 O 3 NMs showed that the conduction band minimum and the valence band maximum states were shifted nearly linearly with the applied uniaxial strain, which caused changes in the optical properties of the β-Ga 2 O 3 NM. We also found that nano-gaps in the β-Ga 2 O 3 NM play a crucial role in enhancing the photoresponsivity of the β-Ga 2 O 3 NM PD under bending conditions due to the secondary light absorption caused by reflected light from the nano-gap surfaces. Therefore, this research provides a viable route to realize high-performance flexible photodetectors, which are one of the indispensable components in future flexible sensor systems.