Disulfide reduction allosterically destabilizes the β-ladder sub-domain assembly within the NS1 dimer of ZIKV

Abstract

AbstractThe Zika virus (ZIKV) was responsible for a recent debilitating epidemic that till date has no cure. A potential way to reduce ZIKV virulence is to limit the action of the non-structural proteins involved in its viral replication. One such protein, NS1, encoded as a monomer by the viral genome, plays a major role via symmetric oligomerization. We examine the homodimeric structure of the dominant β-ladder segment of NS1 with extensive all atom molecular dynamics. We find it stably bounded by two spatially separated interaction clusters (C1 and C2) with significant differences in the nature of their interactions. Four pairs of distal, intra-monomeric disulfide bonds are found to be coupled to the stability, local structure, and wettability of the interfacial region. Symmetric reduction of the intra-monomeric disulfides triggers marked dynamical heterogeneity, interfacial wettability and asymmetric salt bridging propensity. Harnessing the model-free Lipari-Szabo based formalism for estimation of conformational entropy (Sconf), we find clear signatures of heterogeneity in the monomeric conformational entropies. The observed asymmetry, very small in the unperturbed state, expands significantly in the reduced states. This allosteric effect is most noticeable in the electrostatically bound C2 cluster that underlies the greatest stability in the unperturbed state. Allosteric induction of conformational and thermodynamic asymmetry is expected to affect the pathways leading to symmetric higher ordered oligomerization, and thereby affect crucial replication pathways.Statement of significanceControlling viral pathogenesis remains a challenge in the face of modern-day epidemics. Though cumbersome and fraught with misleads, most therapeutic endeavors lean towards the design of drug molecules targeting specific proteins involved in viral pathogenesis. This work demonstrates an alternative approach, namely the usage of allosteric intervention to disrupt the binding integrity of the primary domain of the non-structural NS1 protein dimer crucially important in ZIKV virulence. The intervention, triggered by symmetric reduction of the internal monomeric disulfide bonds, results in weakening and distortion of the distal binding interfaces. It further introduces marked structural and entropic asymmetry within the homooligomeric unit, precluding the formation of higher ordered oligomers of high symmetry. The results have important ramifications for consolidated efforts at limiting ZIKV virulence.