报告题目：Conformationally-driven enzyme design
报告人：Sílvia Osuna ICREA Researcher, University of Girona
时间：2021年11月26日16:00
地点：曾呈奎楼3楼B311
报告摘要：
Enzymes exist as an ensemble of conformational states, whose populations can be shifted by substrate binding, allosteric interactions, but also by introducing mutations to their sequence. Tuning the populations of the enzyme conformational states through mutation enables evolution towards novel activity. A common feature observed in many laboratory-evolved enzymes, is the introduction of remote mutations from the catalytic center, which often have a profound effect in the enzyme catalytic activity.
In this talk, our new computational tools based on inter-residue correlations from microsecond time-scale Molecular Dynamics (MD) simulations and enhanced sampling techniques are applied in Tryptophan synthase (TrpS) complex. TrpS is composed of TrpA and TrpB subunits, which allosterically activate each other and have no activity when isolated. We show how distal mutations introduced in TrpS resuscitate the allosterically-driven conformational regulation and alter the populations and rates of exchange between multiple conformational states, which are essential for the multistep reaction pathway of the enzyme. The exploration of the conformational landscape of TrpS is key for identifying conformationally-relevant amino acid residues of TrpB distal from the active site. We predict positions crucial for shifting the inefficient conformational ensemble of the isolated TrpB to a productive ensemble through intra-subunit allosteric effects. The experimental validation of the new conformationally-driven TrpB design demonstrates its superior stand-alone activity in the absence of TrpA. Our work evidences that the current challenge of distal active site prediction for enhanced function in computational enzyme design can be ultimately addressed.
报告人简介：
Sílvia osuna 是加泰罗尼亚高级研究所(ICREA)的研究教授。她于2010年在University of Girona (赫罗纳大学) 获得博士学位。她的研究兴趣主要是与酶催化和化学反应相关的生化过程。目前已发表88篇研究论文，其中包括高影响因子期刊: 1篇Nature(IF = 43.070) ，1篇Nature Catal. (IF = 41.813) ，1篇Nature Chem. Biol.(IF= 12.154) ，3篇Nature Commun. (IF = 11.880) ，1篇Proc. Nat. Acad. Sci. USA (IF = 9.580) ，5篇 Angew. Chem. Int. Ed. (IF= 12.257) ，12篇 J. Am. Chem. Soc. (IF = 14.695)，总引用超过2700。
