从头设计TIM桶蛋白：关于稳定化、多样化和功能化策略的见解
Designing de novo TIM Barrels: Insights into Stabilization, Diversification, and Functionalization Strategies
AI总结：
本综述探讨TIM桶折叠作为蛋白质设计关键模型的作用，涵盖从头设计的历史与近期进展，分析功能化多样化的挑战及当前方法，支持整合物理与AI驱动的综合优化策略，强调其在定制酶设计及学科交叉中的价值。
摘要：
TIM桶折叠是自然界中最多样化且广泛存在的蛋白质折叠之一，具有多种催化活性和功能，同时也是蛋白质生物化学和工程学中的模型系统。本综述探讨了其作为蛋白质设计关键折叠模型的作用，尤其在应对稳定化和功能化挑战方面。我们讨论了从头TIM桶设计的历史和近期进展，从标志性的sTIM11创建到多样化变体的开发，特别关注深化对调节该结构序列-结构-功能关系的决定因素的理解。此外，鉴于缺乏天然样活性位点特征，我们探讨了为何从头TIM桶向功能化的多样化仍是主要挑战。当前方法聚焦于整合结构延伸、修饰环以及使用前沿AI策略来创建具有定制特征的支架。尽管取得显著进展，实现酶活性从头TIM桶被证明是困难的，仅近期突破展示了功能化设计。我们讨论了逐步功能化方法的局限性，并支持同时优化支架结构和活性位点形状的综合方法，该方法同时使用物理驱动和AI驱动的方法。通过结合计算和实验见解，我们强调TIM桶是定制酶设计的强大模板，也是探索蛋白质生物化学、生物物理学和设计交叉领域的模型系统。
英文摘要：
The TIM-barrel fold is one of the most versatile and ubiquitous protein folds in nature, hosting a wide variety of catalytic activities and functions while serving as a model system in protein biochemistry and engineering. This review explores its role as a key fold model in protein design, particularly in addressing challenges in stabilization and functionalization. We discuss historical and recent advances in de novo TIM barrel design from the landmark creation of sTIM11 to the development of the diversified variants, with a special focus on deepening our understanding of the determinants that modulate the sequence-structure-function relationships of this architecture. Also, we examine why the diversification of de novo TIM barrels towards functionalization remains a major challenge, given the absence of natural-like active site features. Current approaches have focused on incorporating structural extensions, modifying loops, and using cutting-edge AI-based strategies to create scaffolds with tailored characteristics. Despite significant advances, achieving enzymatically active de novo TIM barrels has been proven difficult, with only recent breakthroughs demonstrating functionalized designs. We discuss the limitations of stepwise functionalization approaches and support an integrated approach that simultaneously optimizes scaffold structure and active site shape, using both physical- and AI-driven methods. By combining computational and experimental insights, we highlight the TIM barrel as a powerful template for custom enzyme design and as a model system to explore the intersection of protein biochemistry, biophysics, and design.
机构、总结、中文摘要均由AI分析而来，可能存在错误，请以论文正文为准。
