多肽协同作用下淀粉样成核的粗粒化模拟  

Coarse-Grained Simulation of Amyloid Nucleation under Cooperative Effects of Peptides

作　　者：孙吴雪鹏 吴凯 修鹏 SUN Wuxuepeng;WU Kai;XIU Peng(Department of Engineering Mechanics,Zhejiang University,Hangzhou 310027,China;School of Physical Sciences,University of Chinese Academy of Sciences,Beijing 100049,China)

机构地区：[1]浙江大学工程力学系,杭州310027 [2]中国科学院大学物理科学学院,北京100049

出　　处：《医用生物力学》2023年第2期236-241,254,共7页Journal of Medical Biomechanics

基　　金：国家自然科学基金项目(12174337,11932017);中央高校基本科研业务费专项资金(2017QNA4033)。

摘　　要：目的探究考虑协同作用的多肽构象转变能力对多肽成核及相关产物的影响。方法基于淀粉样多肽的两态(可溶态和β纤维化态)粗粒化模型,分别考虑协同作用(局域浓度)对多肽构象转变能力的两种影响(抑制和促进构象转变),通过蒙特卡罗模拟,分析多肽间协同作用对淀粉样成核的调控。结果对于协同作用抑制多肽构象转变的情况,淀粉样成核只在一定多肽浓度区间内、具有特定大小的寡聚体内才易发生,且出现通路寡聚体和非通路寡聚体共存的现象;而对于协同作用促进多肽构象转变的情况,观察到在低至4μmol/L生理浓度下,体系仍然可以形成原纤维。结论本文引入局域浓度对淀粉样多肽构象转变的影响,使多肽的粗粒化模型更加接近真实情况,观察到一些此前未见报道的新奇现象。研究结果有助于更好理解淀粉样多肽的纤维化机制,并为面向神经退行性疾病的治疗策略提供理论借鉴。Objective To explore the cooperative effect fromβ-propensity of amyloidogenic peptides on amyloid nucleation and its related products.Methods Based on a coarse-grained model for amyloidogenic peptides containing two states(a soluble state and aβ-sheet-forming state),with the consideration of two kinds of cooperative effects onβ-propensity of peptides(inhibiting and promoting the conformational conversion of peptides),the regulation of cooperative effects from amyloidogenic peptides on amyloid nucleation was analyzed through Monte Carlo simulations.Results In the case of the cooperative effect inhibiting the conformational conversion of peptides,amyloid nucleation occurred only within a certain interval of the peptide concentration,as well as inside the oligomers with certain sizes.Besides,the coexistence of on-pathway and off-pathway oligomers was observed.In the case of the cooperative effect promoting the conformational conversion of peptides,theβ-sheet protofibril could be observed at physiological concentration as low as 4μmol/L.Conclusions In this study,a more realistic coarse-grained model for amyloidogenic peptides was developed by introducing the cooperative effects of local concentration onβ-propensity of amyloidogenic peptides,with observation of some intriguing phenomena not reported in previous simulations.The research findings not only improve current understandings about the mechanism of amyloid formation,but also provide theoretic references for the therapeutic strategies for curing neurodegenerative diseases.

关 键 词：淀粉样多肽 多肽聚集 淀粉样成核 纤维化 粗粒化模型 蒙特卡罗模拟 

分 类 号：R318.01[医药卫生—生物医学工程]