Department of Chemistry, University of Cambridge, Cambridge, United Kingdom.
Biophys J. 2012 Jan 4;102(1):158-67. doi: 10.1016/j.bpj.2011.12.003. Epub 2012 Jan 3.
The characterization of the structural dynamics of proteins, including those that present a substantial degree of disorder, is currently a major scientific challenge. These dynamics are biologically relevant and govern the majority of functional and pathological processes. We exploited a combination of enhanced molecular simulations of metadynamics and NMR measurements to study heterogeneous states of proteins and peptides. In this way, we determined the structural ensemble and free-energy landscape of the highly dynamic helix 1 of the prion protein (PrP-H1), whose misfolding and aggregation are intimately connected to a group of neurodegenerative disorders known as transmissible spongiform encephalopathies. Our combined approach allowed us to dissect the factors that govern the conformational states of PrP-H1 in solution, and the implications of these factors for prion protein misfolding and aggregation. The results underline the importance of adopting novel integrated approaches that take advantage of experiments and theory to achieve a comprehensive characterization of the structure and dynamics of biological macromolecules.
蛋白质结构动力学的特征描述，包括那些具有显著无序程度的蛋白质，目前是一个重大的科学挑战。这些动力学在生物学上具有相关性，并控制着大多数功能和病理过程。我们利用增强型分子动力学的元动力学模拟和 NMR 测量相结合的方法来研究蛋白质和肽的异质态。通过这种方式，我们确定了朊病毒蛋白（PrP-H1）高度动态螺旋 1 的结构组合和自由能景观，其错误折叠和聚集与一组称为传染性海绵状脑病的神经退行性疾病密切相关。我们的综合方法使我们能够剖析控制 PrP-H1 在溶液中构象状态的因素，以及这些因素对朊病毒蛋白错误折叠和聚集的影响。研究结果强调了采用新的综合方法的重要性，这些方法利用实验和理论来实现对生物大分子结构和动力学的全面描述。
