Nguyen Hung D, Hall Carol K
Department of Chemical and Biomolecular Engineering, North Carolina State University, Raleigh, North Carolina 27695-7905, USA.
Biophys J. 2004 Dec;87(6):4122-34. doi: 10.1529/biophysj.104.047159. Epub 2004 Oct 1.
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-KA14K-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.
淀粉样纤维是细胞内和细胞外蛋白质沉积物的结构成分，这些沉积物与多种人类疾病相关，包括阿尔茨海默病、帕金森病和朊病毒病。在这项工作中，我们使用新开发的非晶格中分辨率蛋白质模型PRIME研究纤维形成的热力学。该模型足够简单，能够处理大型多链系统，同时在与恒温间断分子动力学（一种替代传统分子动力学的快速方法）结合使用时，能对蛋白质动力学进行相当逼真的描述。我们使用副本交换方法，在很宽的温度和肽浓度范围内，对包含96个Ac-KA14K-NH2肽的系统进行平衡模拟。基于测量得到的热容、回转半径以及形成各种结构的肽的百分比，构建了温度-浓度平面上的相图，描绘出每种结构稳定的区域。有四个不同的单相区域：α-螺旋、纤维、非纤维β-折叠片和无规卷曲；以及四个两相区域：无规卷曲/非纤维β-折叠片、无规卷曲/纤维、纤维/非纤维β-折叠片和α-螺旋/非纤维β-折叠片。α-螺旋区域处于低温和低浓度。非纤维β-折叠片区域处于中等温度和低浓度，并且随着浓度增加向更高温度扩展。纤维区域出现在中等温度和中等浓度，并且随着肽浓度增加向更低温度扩展。无规卷曲区域处于高温和所有浓度；该区域随着浓度增加向更高温度移动。
