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模型蛋白Trp-cage残基互作及外在因素对其结构折叠稳定性影响的研究

Computational and experimental studies on the influence of the Trp-cage inter-residue interactions and other external factors on its structural and folding stability
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摘要 蛋白质折叠驱动力主要取决于结构上残基间的相互作用,尤其是其侧链间的作用.迷你蛋白Trp-cage结构典型且可快速折叠,是理论和实验研究蛋白质折叠的理想模型.尽管该蛋白仅由20个氨基酸组成,但其结构中残基间的相互作用甚为复杂且侧链类型多样.由于现有力场参数对其相互作用描述的精度问题,其折叠模型仍有分歧.本文以模型蛋白Trp-cage为例,首先概述了该蛋白自设计提出以来所报道的所有结构体系及其相应突变体的研究情况,并分析了其TC5b和TC10b两个经典体系的内在残基作用网络和侧链特性;然后详细讨论了其折叠机制模型类型的研究情况,并探讨了不同折叠模型之间的相互转换及其与模拟温度和力场之间的关系;最后从内在残基侧链特性和外在环境因素两个角度讨论了其对结构稳定和折叠动力学行为的影响.各影响因素及其协同效应的阐明不仅有助于揭示蛋白质结构平衡稳定和快速折叠的驱动力成因,也为其进一步结构调控和优化设计提供了理论指导. The major driving force of protein folding depends on their inter-residue interactions,especially for sidechain-sidechain interactions.The Trp-cage is a fast-folding mini-protein,which has already been acknowledged as an ideal model for tackling complicated foldingrelated problems of proteins.Although this protein model is merely composed of 20 amino acid residues,it exhibits an extremely complex interaction network between residues with different types of sidechain orientation.Because current force fields exhibit different degrees of accuracy inadequacies in the descriptions of atomic interactions,it remains a matter of debate at what stage of folding the helix,hydrophobic cluster and salt-bridge is being conclusively formed in its possible folding mechanisms.The structures and mutations of all the Trp-cage system reported since 2002 are summarized in this paper,and its two typical structures(TC5b and TC10b)are taken as examples to summarize the composition and types of their inter-residue interactions as well as the sidechain features and orientations.Meanwhile,the recent computational and experimental studies of several possible folding mechanisms are also generalized and discussed,and their relationships with simulation temperature and force field as well as the switching from one folding pathway to the other are also discussed in detail.Finally,the effects of numerous factors on structural stability and folding dynamics have been elaborately discussed,including different types of inter-residue interactions(such as salt-bridge,hydrophobic and hydrogen-bonding interactions)and environmental factors(such as temperature,pressure,pH and other potential factors).We also propose that the clarification of the above factors and their synergistic effects are beneficial not only to reveal the driving force of protein stabilization and rapid formation,but also to provide theoretical guidance for further structural regulation and optimal design.
作者 吴晓敏 张孝春 汪萌† 黄卓然 张兴旺 张强 徐成振 WU XiaoMin;ZHANG XiaoChun;WANG Meng;HUANG ZhuoRan;ZHANG XingWang;ZHANG Qiang;XU ChengZhen(Anhui Province Key Laboratory of Pollutant Sensitive Materials and Environmental Remediation,College of Life Sciences,Huaibei Normal University,Huaibei 235000,China;College of Computer Science and Technology,Huaibei Normal University,Huaibei 235000,China)
出处 《中国科学:生命科学》 CSCD 北大核心 2021年第2期135-150,共16页 Scientia Sinica(Vitae)
基金 国家自然科学基金(批准号:31500594) 安徽省自然科学基金(批准号:1908085QF286,1608085MC49) 安徽省高校省级自然科学研究重点项目(批准号:KJ2020A0037,KJ2020A0031,KJ2017A373) 安徽省高校优秀青年人才支持计划(批准号:gxyq2018163) 安徽省高校优秀青年骨干人才国外访学研修项目。
关键词 模型蛋白Trp-cage 残基相互作用 折叠模型 残基突变 侧链位置与特性 Trp-cage mini-protein model inter-residue interactions folding model residue mutation sidechain orientation and property
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