Structure and Dynamics of the Misfolding Intermediate in the Pathogenic T183A Prion Protein Mutant

IF 5.5 1区 化学 Q2 CHEMISTRY, PHYSICAL
Carmen Biancaniello, , , Alessandro Emendato, , and , Alfonso De Simone*, 
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引用次数: 0

Abstract

Characterizing high-energy conformations in protein molecules is crucial to delineate the nature of dynamic processes that underlie biological activity, as these elusive species often play critical roles in fundamental mechanisms of the cell, such as enzyme catalysis or protein folding and aggregation, among many others. In this context, the integration of molecular simulations with experimental biophysics represents a powerful strategy to delineate complex conformational landscapes, enabling the study of transient conformations at atomic resolution. Here, we characterized intermediate states along the misfolding pathway of the human prion protein (PrP) variant T183A, which is associated with familial Creutzfeldt–Jakob disease. Using replica-averaged molecular dynamics simulations, restrained with nuclear magnetic resonance chemical shifts, we obtained structural ensembles showing enhanced conformational heterogeneity for the T183A variant compared with the WT protein. The mutant ensemble was found to populate partially misfolded states characterized by disruption of the β-sheet and local unfolding of key helical regions of the protein. Additionally, dynamic cross-correlation analyses evidenced significant loss of cooperative fluctuations across secondary structure elements, delineating how structural destabilization in the T183A variant leads to the insurgence of misfolding intermediates. Collectively, these findings provide critical insights into the underlying mechanisms of T183A-induced PrP misfolding and its consequent aggregation into amyloid fibrils.

致病性T183A朊蛋白突变体中错误折叠中间体的结构和动力学
描述蛋白质分子中的高能构象对于描述生物活性背后的动态过程的本质至关重要,因为这些难以捉摸的物种通常在细胞的基本机制中发挥关键作用,例如酶催化或蛋白质折叠和聚集等。在这种情况下,分子模拟与实验生物物理学的结合代表了描绘复杂构象景观的有力策略,使原子分辨率的瞬态构象研究成为可能。在这里,我们表征了与家族性克雅氏病相关的人类朊病毒蛋白(PrP)变体T183A错误折叠途径的中间状态。利用复制平均分子动力学模拟,在核磁共振化学位移的约束下,我们获得了与WT蛋白相比,T183A变体的结构整体显示出增强的构象异质性。发现突变合体填充部分错误折叠状态,其特征是β-片的破坏和蛋白质关键螺旋区域的局部展开。此外,动态相互关联分析证明了二级结构元素之间的协同波动的显著损失,描绘了T183A变异的结构不稳定如何导致错误折叠的中间产物的暴动。总的来说,这些发现为t183a诱导的PrP错误折叠及其随后聚集成淀粉样原纤维的潜在机制提供了重要的见解。
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来源期刊
Journal of Chemical Theory and Computation
Journal of Chemical Theory and Computation 化学-物理:原子、分子和化学物理
CiteScore
9.90
自引率
16.40%
发文量
568
审稿时长
1 months
期刊介绍: The Journal of Chemical Theory and Computation invites new and original contributions with the understanding that, if accepted, they will not be published elsewhere. Papers reporting new theories, methodology, and/or important applications in quantum electronic structure, molecular dynamics, and statistical mechanics are appropriate for submission to this Journal. Specific topics include advances in or applications of ab initio quantum mechanics, density functional theory, design and properties of new materials, surface science, Monte Carlo simulations, solvation models, QM/MM calculations, biomolecular structure prediction, and molecular dynamics in the broadest sense including gas-phase dynamics, ab initio dynamics, biomolecular dynamics, and protein folding. The Journal does not consider papers that are straightforward applications of known methods including DFT and molecular dynamics. The Journal favors submissions that include advances in theory or methodology with applications to compelling problems.
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