蛋白质聚集机制的多尺度模拟及动力学网络分析研究
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- 英文论文题名：Insights into Protein Aggregation Revealed by Multi-scaled Simulations and Kinetic Network Analysis
- 论文作者：韩伟
- 英文论文作者：Wei Han ; School of Chemical Biology and Biotechnology ; Peking University Shenzhen Graduate School
- 年：2016
- 作者机构：北京大学深圳研究生院化学生物学与生物技术学院;
- 论文关键词：分子动力学模拟 ; 淀粉样沉淀 ; 蛋白质-蛋白质相互作用
- 会议召开时间：2016-07-01
- 会议录名称：中国化学会第30届学术年会摘要集-第十九分会：化学中的量子与经典动力学
- 语种：中文
- 分类号：R363
- 学会代码：ZGHY
- 会议名称：中国化学会第30届学术年会-第十九分会 ; 化学中的量子与经典动力学
- 会议地点：中国辽宁大连
- 主办单位：中国化学会
- 学会名称：中国化学会
- 页数：1
- 文件大小：209k
- 原文格式：D
- 会议级别：全国
摘要
蛋白质聚集与Ⅱ型糖尿病及其他诸多神经退化性疾病密切相关。如何有效防止蛋白质的聚集是治疗相关疾病的关键,而这有赖于研究者深入理解蛋白质聚集的分子机制。然而蛋白聚集经历多个步骤,各个步骤又牵涉复杂的构象变化,这给实验表征带来了巨大的困难。另一方面,由于蛋白聚集的时间尺度远在毫秒量级以上,目前运用计算模拟研究相关构象变化极具挑战性。针对这些挑战,我们开发了一套结合多尺度模型、增强抽样及动力学网络分析等手段的计算方法,并对蛋白聚集过程中早期寡聚体形成、成熟纤维生长以及蛋白在纤维表面上的构象转换等几个关键步骤进行了计算模拟研究。这些研究使我们对聚集过程中分子内结构变化与分子间相互作用的关系、纤维非对称生长的原因以及纤维表面催化蛋白构象变化的机制等重要的问题有了更为深入的认识,并为探索抑制蛋白聚集的可能途径提供了新的思路。
Amyloid deposits characterize many diseases, including particularly neurodegenerative diseases such as Alzheimer's, Parkinson's, and Huntington's diseases, in addition to Type II diabetes, each associated with the aggregation of a distinct protein. Protein aggregation comprises many steps, involving structural transitions to various intermediates. The molecular basis of these structural transitions is valuable for seeking means of the prevention of protein aggregation for disease treatment, but remains poorly understood. On the computational side, the main challenge is the need for simulations on long timescales far beyond the reach of conventional methods. My talk will be focused on our efforts in the development of computational methods that combine multi-facet approaches to overcome the computational challenge. The methods have been applied to yield new insights into several key steps of protein aggregation. In addition, I will discuss our recent effort in understanding the molecular basis of the prevention of protein aggregation.
Amyloid deposits characterize many diseases, including particularly neurodegenerative diseases such as Alzheimer's, Parkinson's, and Huntington's diseases, in addition to Type II diabetes, each associated with the aggregation of a distinct protein. Protein aggregation comprises many steps, involving structural transitions to various intermediates. The molecular basis of these structural transitions is valuable for seeking means of the prevention of protein aggregation for disease treatment, but remains poorly understood. On the computational side, the main challenge is the need for simulations on long timescales far beyond the reach of conventional methods. My talk will be focused on our efforts in the development of computational methods that combine multi-facet approaches to overcome the computational challenge. The methods have been applied to yield new insights into several key steps of protein aggregation. In addition, I will discuss our recent effort in understanding the molecular basis of the prevention of protein aggregation.
引文
[1]Jucker,M.;Walker,L.C.Nature 2013,501:45.
[2]Arosio,P.;Vendruscolo,M.;Dobson,C.M.;Knowles,T.P.J.Trends Pharmacol.Sci.2014,35:127.
[3]Han,W.;Schulten,K.J.Am.Chem.Soc.2014,136:12450.
[4]Yu,H.;Han,W.;Ma,W.;Schulten,K.J.Chem.Phys.2015,143:243142(共同一作).
[5]Han,W.;Schulten,K.J.Chem.Theory Comput.2012,8:4413.
[2]Arosio,P.;Vendruscolo,M.;Dobson,C.M.;Knowles,T.P.J.Trends Pharmacol.Sci.2014,35:127.
[3]Han,W.;Schulten,K.J.Am.Chem.Soc.2014,136:12450.
[4]Yu,H.;Han,W.;Ma,W.;Schulten,K.J.Chem.Phys.2015,143:243142(共同一作).
[5]Han,W.;Schulten,K.J.Chem.Theory Comput.2012,8:4413.