翻译后修饰对于蛋白质结构动态与稳定性的影响——实验和理论的探索  

How post-translational modifications impact protein dynamics and stability—experimental and theoretical investigations

作　　者：李煜昊 陈海龙[2] 唐淳 Yuhao Li;Hailong Chen;Chun Tang(College of Chemistry and Molecular Engineering,Peking University,Beijing 100871,China;Institute of Physics,Chinese Academy of Sciences,Beijing 100190,China)

机构地区：[1]北京大学化学与分子工程学院,北京100871 [2]中国科学院物理研究所,北京100190

出　　处：《中国科学:化学》2025年第4期937-948,共12页SCIENTIA SINICA Chimica

基　　金：国家自然科学基金重大研究计划(编号:92353304)资助项目。

摘　　要：翻译后修饰(PTMs)在调控蛋白质结构动态、稳定性及功能方面发挥着关键作用.常见的修饰类型如磷酸化、糖基化、乙酰化和泛素化等,通过共价修饰改变蛋白质的局部结构、静电相互作用、疏水性及氢键网络,进而调控蛋白质的稳定性及其在细胞内的降解速率.不同PTMs之间通过协同作用或顺序修饰进一步增加了蛋白质功能调控的复杂性.为深入研究PTMs的影响,研究者已开发并应用多种实验技术,包括红外光谱(IR)、核磁共振(NMR)和氢氘交换质谱(HDX-MS)等,这些方法能够从不同分辨率水平揭示PTMs诱导的蛋白质构象和动态变化,表征PTMs引起的局部结构扰动,还能揭示别构效应及低丰度激发态构象对蛋白质稳定性的影响,以及PTMs对蛋白质的去折叠和聚集过程的影响.在生物医药应用中,PTMs通过实现靶向递送和降低免疫原性来增强治疗性蛋白质的性能,从而提高药物的疗效和安全性.总之,通过深入研究PTMs的分子机制,结合多学科技术手段进行整合表征,将为设计和开发更高效、更稳定的蛋白质药物及治疗策略提供重要理论依据和技术支持.Post-translational modifications(PTMs)play crucial regulatory roles in modulating protein structural dynamics,stability,and functionality.Common modifications such as phosphorylation,glycosylation,acetylation,and ubiquitination covalently modify proteins,altering their local structures,electrostatic interactions,hydrophobicity,and hydrogen-bonding patterns.These changes influence protein stability and intracellular degradation rates.The interplay between various PTMs through synergistic or sequential modifications adds further complexity to the regulation of protein functions.To investigate PTM effects,researchers have employed a multitude of experimental techniques including infrared spectroscopy(IR),nuclear magnetic resonance(NMR),and hydrogen-deuterium exchange mass spectrometry(HDX-MS),which unveil PTM-induced conformational and dynamic changes at multiple resolutions.These methods can capture localized structural perturbations and allosteric effects,as well as lowly populated excitedstates that impact protein stability.Moreover,it has been shown that PTMs may suppress protein unfolding and aggregation.In biopharmaceutical applications,PTMs enhance therapeutic protein performance by enabling targeted delivery and reduced immunogenicity,thereby improving drug efficacy and safety.In conclusion,in-depth investigation of the molecular mechanisms underlying PTMs,coupled with integrated characterization with multidisciplinary technical approaches,will allow researchers to design and develop better protein therapeutics and treatment strategies.

关 键 词：蛋白质 翻译后修饰 结构动态 热力学耦合 谱学方法 

分 类 号：Q51[生物学—生物化学]