Dengue represents a substantial public health burden, particularly in low-resource countries. Non-structural protein 3 (NS3) is a multifunctional protein critical in the virus life cycle and has been identified as a promising anti-viral drug target. Despite recent crystallographic studies of the NS3 helicase domain, only subtle structural nucleotide-dependent differences have been identified, such that its coupled ATPase and helicase activities remain mechanistically unclear. Here we use molecular dynamics simulations to explore the nucleotide-dependent conformational landscape of the Dengue virus NS3 helicase and identify substantial changes in the protein flexibility during the ATP hydrolysis cycle. We relate these changes to the RNA-protein interactions and proposed translocation models for other monomeric helicases. Furthermore, we report a novel open-loop conformation with a likely escape route for Pi after hydrolysis, providing new insight into the conformational changes that underlie the ATPase activity of NS3.

中文翻译：

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登革热NS3解旋酶的核苷酸依赖性动力学。

登革热给公共卫生带来沉重负担，尤其是在资源匮乏的国家。非结构蛋白3（NS3）是病毒生命周期中至关重要的多功能蛋白，已被确定为有前途的抗病毒药物靶标。尽管最近对NS3解旋酶结构域的晶体学研究，仅鉴定了细微的结构核苷酸依赖性差异，使得其偶联的ATPase和解旋酶活性在机械上仍不清楚。在这里，我们使用分子动力学模拟来探索登革热病毒NS3解旋酶的核苷酸依赖性构象格局，并确定ATP水解过程中蛋白质柔韧性的实质性变化。我们将这些变化与RNA蛋白质相互作用和其他单体解旋酶的拟议易位模型联系起来。此外，