2DIR Spectroscopy of Human Amylin Fibrils Reflects Stable 尾-Sheet Structure

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• 作者：Lu Wang ; Chris T. Middleton ; Sadanand Singh ; Allam S. Reddy ; Ann M. Woys ; David B. Strasfeld ; Peter Marek ; Daniel P. Raleigh ; Juan J. de Pablo ; Martin T. Zanni ; James L. Skinner
• 刊名：Journal of the American Chemical Society
• 出版年：2011
• 出版时间：October 12, 2011
• 年：2011
• 卷：133
• 期：40
• 页码：16062-16071
• 全文大小：1139K
• 年卷期：v.133,no.40(October 12, 2011)
• ISSN：1520-5126

文摘

The aggregation of human amylin to form amyloid contributes to islet 尾-cell dysfunction in type 2 diabetes. Studies of amyloid formation have been hindered by the low structural resolution or relatively modest time resolution of standard methods. Two-dimensional infrared (2DIR) spectroscopy, with its sensitivity to protein secondary structures and its intrinsic fast time resolution, is capable of capturing structural changes during the aggregation process. Moreover, isotope labeling enables the measurement of residue-specific information. The diagonal line widths of 2DIR spectra contain information about dynamics and structural heterogeneity of the system. We illustrate the power of a combined atomistic molecular dynamics simulation and theoretical and experimental 2DIR approach by analyzing the variation in diagonal line widths of individual amide I modes in a series of labeled samples of amylin amyloid fibrils. The theoretical and experimental 2DIR line widths suggest a 鈥淲鈥?pattern, as a function of residue number. We show that large line widths result from substantial structural disorder and that this pattern is indicative of the stable secondary structure of the two 尾-sheet regions. This work provides a protocol for bridging MD simulation and 2DIR experiments for future aggregation studies.