Sandelin Amanda E, Nencini Ricky, Yasar Ekrem, Fudo Satoshi, Stratoulias Vassilis, Kajander Tommi, Ollila O H Samuli
Institute of Biotechnology, University of Helsinki, Helsinki, Finland.
Division of Pharmacology and Pharmacotherapy, Faculty of Pharmacy, University of Helsinki, Helsinki, Finland.
Commun Chem. 2025 Aug 10;8(1):241. doi: 10.1038/s42004-025-01623-x.
Multidomain proteins containing both folded and intrinsically disordered regions are crucial for biological processes, but characterizing their conformational ensembles and dynamics remains challenging. We introduce the Quality Evaluation Based Simulation Selection (QEBSS) protocol, which combines MD simulations with NMR-derived protein backbone N T and T spin relaxation times and hetNOE values to interpret conformational ensembles and dynamics of multidomain proteins. We demonstrate the practical advantage of QEBSS by characterizing four flexible multidomain proteins: calmodulin, EN2, MANF, and CDNF. These biologically important proteins have been difficult to study due to their flexible nature. Our findings reveal new insights into their conformational landscapes and dynamics, providing mechanistic understanding of their biological functions. QEBSS offers quantitative quality evaluation of simulations and a systematic approach for resolving conformational ensembles of multidomain proteins with heterogeneous dynamics. Given the importance of such proteins in biology, biotechnology, and materials science, QEBSS should benefit fields from drug design to novel materials development.
包含折叠区域和内在无序区域的多结构域蛋白质对生物过程至关重要，但表征它们的构象集合和动力学仍然具有挑战性。我们引入了基于质量评估的模拟选择（QEBSS）方案，该方案将分子动力学（MD）模拟与核磁共振（NMR）衍生的蛋白质主链N T和T自旋弛豫时间以及异核Overhauser效应（hetNOE）值相结合，以解释多结构域蛋白质的构象集合和动力学。我们通过表征四种柔性多结构域蛋白质：钙调蛋白、EN2、MANF和CDNF，证明了QEBSS的实际优势。这些具有生物学重要性的蛋白质由于其柔性本质而难以研究。我们的研究结果揭示了它们构象景观和动力学的新见解，为其生物学功能提供了机制理解。QEBSS提供了模拟的定量质量评估，以及一种解决具有异质动力学的多结构域蛋白质构象集合的系统方法。鉴于此类蛋白质在生物学、生物技术和材料科学中的重要性，QEBSS应该会使从药物设计到新型材料开发等领域受益。
