Phase diagrams describing fibrillization by polyalanine peptides
Phase diagrams describing fibrillization by polyalanine peptides
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DOI：
10.1529/biophysj.104.047159
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发表时间：
2004-12-01
影响因子：
3.4
通讯作者：
Hall, CK
中科院分区：
文献类型：
--
作者：
Nguyen, HD;Hall, CK
淀粉样原纤维是与多种人类疾病（包括阿尔茨海默病、帕金森病和朊病毒疾病）相关的细胞内和细胞外蛋白沉积物的结构组分。在这项工作中，我们使用我们新开发的非晶格中间分辨率蛋白质模型，PRIME研究原纤维形成的热力学。该模型是足够简单，允许治疗的大型多链系统，同时保持一个相当现实的描述蛋白质动力学结合使用时，恒温不连续的分子动力学，快速替代传统的分子动力学。我们使用复制交换方法对含有96 Ac-KA（14）K-NH 2肽的系统在宽范围的温度和肽浓度下进行平衡模拟。基于热容、回转半径和形成各种结构的肽的百分比的测量值，构建温度-浓度平面中的相图，描绘每个结构稳定的区域。存在四个不同的单相区域：α-螺旋、原纤维、非原纤维β-片层和无规卷曲;以及四个两相区域：无规卷曲/非原纤维β-片层、无规卷曲/原纤维、原纤维/非原纤维β-片层和α-螺旋/非原纤维β-片层。α-螺旋区域处于低温和低浓度。非原纤维β-折叠区处于中等温度和低浓度下，并随着浓度的增加而膨胀到更高的温度。原纤维区域在中等温度和中等浓度下出现，并且随着肽浓度的增加而扩展至较低。无规卷曲区域在高温和所有浓度下;随着浓度的增加，该区域向更高的温度移动。
Amyloid fibrils are the structural components underlying the intra- and extracellular protein deposits that are associated with a variety of human diseases, including Alzheimer's, Parkinson's, and the prion diseases. In this work, we examine the thermodynamics of fibril formation using our newly-developed off-lattice intermediate-resolution protein model, PRIME. The model is simple enough to allow the treatment of large multichain systems while maintaining a fairly realistic description of protein dynamics when used in conjunction with constant-temperature discontinuous molecular dynamics, a fast alternative to conventional molecular dynamics. We conduct equilibrium simulations on systems containing 96 Ac-KA(14)K-NH2 peptides over a wide range of temperatures and peptide concentrations using the replica-exchange method. Based on measured values of the heat capacity, radius of gyration, and percentage of peptides that form the various structures, a phase diagram in the temperature-concentration plane is constructed delineating the regions where each structure is stable. There are four distinct single-phase regions: alpha-helices, fibrils, nonfibrillar beta-sheets, and random coils; and four two-phase regions: random coils/nonfibrillar beta-sheets, random coils/fibrils, fibrils/nonfibrillar beta-sheets, and alpha-helices/nonfibrillar beta-sheets. The alpha-helical region is at low temperature and low concentration. The nonfibrillar beta-sheet region is at intermediate temperatures and low concentrations and expands to higher temperatures as concentration is increased. The fibril region occurs at intermediate temperatures and intermediate concentrations and expands to lower as the peptide concentration is increased. The random-coil region is at high temperatures and all concentrations; this region shifts to higher temperatures as the concentration is increased.