Interactions of the nsP3 proteins of CHIKV with the human host protein NAP1 plays a significant role in viral pathogenesis – An in silico study

Abstract

Non-structural protein 3 (nsP3) of Chikungunya virus (CHIKV) is known to interact with numerous mammalian host proteins during the course of its infection. Two such proteins are NAP1L1 and NAP1L4 (nucleosome assembly protein 1 like proteins 1 and 4), which are known to bind at the C-terminal domain of nsP3 and redundantly stimulate replication. However, the detailed mechanism of this pro-viral effect is not fully understood. During the last two decades, ChikV outbreak has occurred in several countries making it a major public health problem. The outbreak strain have shown a higher virulence, and carry specific point mutations in their structural and non-structural proteins, including nsP3. We considered the possibility that the presence of these mutations may cause the nsP3 of the more virulent outbreak strain to interact with the NAP1 proteins differently than that of the less virulent prototype strain. We carried out in silico studies of the interactions of NAP1L1/L4 proteins with the nsP3 proteins of three different strains of CHIKV, one of which is a highly virulent outbreak strain. The results of our structure prediction and docking studies showed that in a less virulent strain, NAP1L4 binds relatively better than NAP1L1 to the C-terminal domain of nsP3. In the more virulent strain, the difference between the bindings of these two proteins was even higher. A Molecular dynamic simulation of the docked complexes of nsP3 with the host NAP1L1 and NAP1L4 proteins for a 100 ns timeframe study over a period of 100 ns validated the reliability of the binding models and further substantiated the differences between the two complexes. Our results suggest that NAP1L4 is possibly a better target than NAP1L1 for designing antiviral drugs against CHIKV infection.