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Partial Intrinsic Disorder Governs the Dengue Capsid Protein Conformational Ensemble
ACS Chemical Biology ( IF 4 ) Pub Date : 2018-05-24 00:00:00 , DOI: 10.1021/acschembio.8b00231
Priscilla L. S. Boon 1, 2, 3 , Wuan Geok Saw 4 , Xin Xiang Lim 2 , Palur Venkata Raghuvamsi 2 , Roland G. Huber 1 , Jan K. Marzinek 1, 2 , Daniel A. Holdbrook 1 , Ganesh S. Anand 2 , Gerhard Grüber 4 , Peter J. Bond 1, 2
Affiliation  

The 11 kDa, positively charged dengue capsid protein (C protein) exists stably as a homodimer and colocalizes with the viral genome within mature viral particles. Its core is composed of four alpha helices encompassing a small hydrophobic patch that may interact with lipids, but approximately 20% of the protein at the N-terminus is intrinsically disordered, making it challenging to elucidate its conformational landscape. Here, we combine small-angle X-ray scattering (SAXS), amide hydrogen–deuterium exchange mass spectrometry (HDXMS), and atomic-resolution molecular dynamics (MD) simulations to probe the dynamics of dengue C proteins. We show that the use of MD force fields (FFs) optimized for intrinsically disordered proteins (IDPs) is necessary to capture their conformational landscape and validate the computationally generated ensembles with reference to SAXS and HDXMS data. Representative ensembles of the C protein dimer are characterized by alternating, clamp-like exposure and occlusion of the internal hydrophobic patch, as well as by residual helical structure at the disordered N-terminus previously identified as a potential source of autoinhibition. Such dynamics are likely to determine the multifunctionality of the C protein during the flavivirus life cycle and hence impact the design of novel antiviral compounds.

中文翻译:

部分固有疾病控制登革衣壳蛋白构象集合体。

11 kDa带正电的登革热衣壳蛋白(C蛋白)作为同型二聚体稳定存在,并与成熟病毒颗粒中的病毒基因组共定位。它的核心由四个α螺旋组成,这些螺旋包含一个可能与脂质相互作用的小的疏水斑块,但是N端大约20%的蛋白质本质上是无序的,因此难以阐明其构象结构。在这里,我们结合了小角度X射线散射(SAXS),酰胺氢-氘交换质谱(HDXMS)和原子分辨率分子动力学(MD)模拟来探测登革热C蛋白的动力学。我们表明,使用针对内在无序蛋白(IDPs)优化的MD力场(FFs)的使用对于捕获其构象景观并验证参考SAXS和HDXMS数据的计算生成的集合是必要的。C蛋白二聚体的代表性集合的特征在于内部疏水性斑块的交替的,钳状的暴露和闭塞以及先前被确定为自抑制的潜在来源的无序的N末端处的残留螺旋结构。这种动力学可能决定黄病毒生命周期中C蛋白的多功能性,从而影响新型抗病毒化合物的设计。内部疏水性膜片的钳状暴露和闭塞,以及先前被确定为自抑制的潜在来源的无序N末端的残留螺旋结构。这种动力学可能决定黄病毒生命周期中C蛋白的多功能性,从而影响新型抗病毒化合物的设计。内部疏水性膜片的钳状暴露和闭塞,以及先前被确定为自抑制的潜在来源的无序N末端的残留螺旋结构。这种动力学可能决定黄病毒生命周期中C蛋白的多功能性,从而影响新型抗病毒化合物的设计。
更新日期:2018-05-24
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