Mpro-C蛋白三维结构域交换的机理:来自分子模拟的线索

SARS coronavirus main protease (Mpro) is a key enzyme involved in the extensive proteolytic processing of the virus? polyproteins. The crystal structure of Mpro reveals that the enzyme exists in two different homo-dimeric forms: a three-dimensional (3D) domain-swapped form; and a non-3D domain-swapped form. The isolated C-terminal domain (Mpro-C) also forms a 3D domain-swapped structure similar to the ful-length protein. Unlike conventional 3D domain-swapped structures, in which the swapped regions are located on the surface, Mpro-C swaps a helix at the core of a folded domain. In this work, we used molecular dynamics simulations and 3D domain-swapping predictions to investigate how a highly buried core helix in the helix bundle structure of Mpro-C can be swapped. We found that both structure-and sequence-based methods failed to predict the location of the hinge loop in Mpro-C and Mpro. Extensive molecular dynamics simulations were performed to investigate the structural properties of the unfolded monomer and the 3D domain-swapped dimer of Mpro-C. We found that, although the swapped region was buried in the native state, it was exposed in the unfolded monomer. Our results suggest that the opening of the swapped region in the ful y or partial y unfolded state may promote interactions between monomers and the formation of domain-swapped dimers.