Department of Chemistry , University of North Texas , Denton , Texas 76201 , United States.
Department of Chemistry , Wayne State University , Detroit , Michigan 48202 , United States.
J Phys Chem B. 2019 Apr 18;123(15):3267-3271. doi: 10.1021/acs.jpcb.9b01694. Epub 2019 Apr 4.
The aggregation of amyloid fibrils can lead to various diseases including Alzheimer's, Parkinson's disease, and transmissible spongiform encephalopathy. Amyloid fibrils can develop from a variety of proteins in the body as they misfold into a primarily β-sheet structure and aggregate. Human lysozyme has been shown to have far reaching effects in the human health-a homologous enzyme, hen egg-white lysozyme, has been shown to denature to a primarily β-sheet structure at low pH and high alcohol content solution. We have studied these systems in atomic-level detail with a combination of constant pH and microsecond long molecular dynamics simulation in explicit solvent, which cumulatively total over 10 μs of simulation time. These studies have allowed us to determine two potential unfolding pathways depending on the protonation state of a key glutamic acid residue as well as the effect of solution dynamics and pH on the unfolding process.
淀粉样纤维的聚集可导致多种疾病，包括阿尔茨海默病、帕金森病和传染性海绵状脑病。淀粉样纤维可以从体内的各种蛋白质中产生，因为它们错误折叠成主要的β-折叠结构并聚集。已经证明，人溶菌酶对人体健康有深远的影响——同源酶，鸡卵清溶菌酶，在低 pH 值和高酒精含量的溶液中已经显示出向主要β-折叠结构变性。我们已经使用在显式溶剂中具有恒定 pH 值和微秒级长分子动力学模拟的组合，以原子级细节研究了这些系统，这些模拟总共累计超过 10 μs 的模拟时间。这些研究使我们能够确定两种潜在的展开途径，这取决于关键谷氨酸残基的质子化状态以及溶液动力学和 pH 值对展开过程的影响。
