Acta Phys. -Chim. Sin. ›› 2012, Vol. 28 ›› Issue (10): 2411-2417.doi: 10.3866/PKU.WHXB201209072

• BIOPHYSICAL CHEMISTRY • Previous Articles     Next Articles

Mechanism of 3D Domain Swapping for Mpro-C: Clues from Molecular Simulations

HUANG Yong-Qi1,2,3, KANG Xue1,4, XIA Bing1,4,5, LIU Zhi-Rong1,2,3   

  1. 1 College of Chemistry and Molecular Engineering, Peking University, Beijing 100871, P. R. China;
    2 State Key Laboratory for Structural Chemistry of Unstable and Stable Species and Beijing National Laboratory for Molecular Sciences (BNLMS), Peking University, Beijing 100871, P. R. China;
    3 Center for Quantitative Biology, Peking University, Beijing 100871, P. R. China;
    4 Beijing Nuclear Magnetic Resonance Center, Peking University, Beijing 100871, P. R. China;
    5 School of Life Sciences, Peking University, Beijing 100871, P. R. China
  • Received:2012-08-13 Revised:2012-09-07 Published:2012-09-26
  • Supported by:

    The project was supported by the National Key Basic Research Program of China (2009CB918500, 2003CB514104) and National Natural Science Foundation of China (20973016, 11021463, 31170682).


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 full-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 fully or partially unfolded state may promote interactions between monomers and the formation of domain-swapped dimers.

Key words: SARS coronavirus, Main protease, Molecular simulation, Domain swapping, Protein-protein interaction, Protein unfolding


  • O641