摘要
易位子辅助膜蛋白插入内质网膜是膜蛋白质生物生成的关键过程。了解不同类分子插入生物膜的机制是预测溶质分子透膜速度的先决条件,这也是药物设计和药理学领域的关键因素。根据插入机制,可以设计插膜肽直接用于疾病治疗,或者作为载体有选择性地将药物靶向特定细胞。自从2004年第1个易位子通道蛋白(Sec)的晶体结构被解析后,近十几年来大量的实验和理论研究,都在致力于揭示Sec辅助膜蛋白插入过程的分子机制。本文总结了过去该领域的实验和分子动力学模拟研究进展,从热力学方面重点分析了造成膜蛋白插入自由能分子动力学模拟计算值,以及实验值间偏差的原因。其中,根据研究条件精确设置模拟参数、插入造成的膜变形对自由能计算有很大的影响;核糖体为新生肽插入到Sec通道过程提供了能量,核糖体与Sec的结合影响Sec侧门的开放程度和Sec通道的结构,从而降低膜插入自由能。Sec辅助膜蛋白插入是一个极其复杂的过程,但整个过程仍然符合热力学和动力学的基本原理,尽管疏水性是Sec辅助膜蛋白质插入的关键性因素,但也不能忽略动力学因素的影响。
Transloconassisted insertion of membrane protein into the endoplasmic reticulum is a key process in membrane protein biogenesis. Understanding how different classes of molecules move across biological membranes is a prerequisite to predict a solute’s permeation rate, which is a critical factor in the fields of drug design and pharmacology. The translocation peptides could be designed as therapeutics directly or as carriers for selective and efficient transport of cargo into targeted cells. Since the first crystal structure of translocon (Sec) was resolved in 2004, numerous experimental and theoretical investigations over the past decade focus on the molecular mechanism of transloconassisted insertion. This paper reviews the recent progress of experiments and molecular dynamics simulations in the field. On the thermodynamics, we lay special stress on analyzing the discrepancy of membrane insertion free energy between experiment and molecular dynamics simulation. The set of computational parameters exactly reflected the experimental conditions and the membrane distortion caused by insertion, which have significant effect on the value of free energy. The ribosome provides energy for the insertion of nascent peptide into Sec channel, and its interaction with Sec affects the opening of lateral gate and the conformation of channel, thus compressing the membrane insertion free energy. The transloconassisted insertion is an extremely complex process primarily driven by thermodynamic and kinetic principles, and their kinetic factors cannot be neglected, although the hydrophobicity scale is predominant.
出处
《中国生物化学与分子生物学报》
CAS
CSCD
北大核心
2018年第12期1257-1265,共9页
Chinese Journal of Biochemistry and Molecular Biology
基金
广西自然科学基金项目(No.2016GXNSFCA380011)
广西高校北部湾石油天然气资源有效利用重点实验室自主课题(No.2015KLOG10)
钦州学院引进高层次人才科研启动项目(No.2018KYQD04)资助.
关键词
膜蛋白质
易位子
膜蛋白插入
自由能
核糖体
membrane protein
translocon
membrane insertion
free energy
ribosome