Mechanism of 3D domain swapping for M pro-C: Clues from molecular simulations

Abstract

SARS coronavirus main protease (M pro) is a key enzyme involved in the extensive proteolytic processing of the virus' polyproteins. The crystal structure of M pro 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 (M pro-C) also forms a 3D domain-swapped structure similar to the full-length protein. Unlike conventional 3D domain-swapped structures, in which the swapped regions are located on the surface, M pro-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 M pro-C can be swapped. We found that both structure- and sequence-based methods failed to predict the location of the hinge loop in M pro-C and M pro. Extensive molecular dynamics simulations were performed to investigate the structural properties of the unfolded monomer and the 3D domain-swapped dimer of M pro-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 fully or partially unfolded state may promote interactions between monomers and the formation of domain-swapped dimers. © Editorial office of Acta Physico-Chimica Sinica.