Chávez-García Cecilia, Hénin Jérôme, Karttunen Mikko
Department of Chemistry, the University of Western Ontario, 1151 Richmond Street, London, Ontario N6A 5B7, Canada.
The Centre of Advanced Materials and Biomaterials Research, the University of Western Ontario, 1151 Richmond Street, London, Ontario N6A 5B7, Canada.
J Chem Inf Model. 2022 Feb 28;62(4):958-970. doi: 10.1021/acs.jcim.1c01354. Epub 2022 Feb 7.
The malfunction of the methyl-CpG binding protein 2 (MeCP2) is associated with the Rett syndrome, one of the most common causes of cognitive impairment in females. MeCP2 is an intrinsically disordered protein (IDP), making its experimental characterization a challenge. There is currently no structure available for the full-length MeCP2 in any of the databases, and only the structure of its MBD domain has been solved. We used this structure to build a full-length model of MeCP2 by completing the rest of the protein via ab initio modeling. Using a combination of all-atom and coarse-grained simulations, we characterized its structure and dynamics as well as the conformational space sampled by the ID and transcriptional repression domain (TRD) domains in the absence of the rest of the protein. The present work is the first computational study of the full-length protein. Two main conformations were sampled in the coarse-grained simulations: a globular structure similar to the one observed in the all-atom force field and a two-globule conformation. Our all-atom model is in good agreement with the available experimental data, predicting amino acid W104 to be buried, amino acids R111 and R133 to be solvent-accessible, and having a 4.1% α-helix content, compared to the 4% found experimentally. Finally, we compared the model predicted by AlphaFold to our Modeller model. The model was not stable in water and underwent further folding. Together, these simulations provide a detailed (if perhaps incomplete) conformational ensemble of the full-length MeCP2, which is compatible with experimental data and can be the basis of further studies, e.g., on mutants of the protein or its interactions with its biological partners.
甲基-CpG结合蛋白2（MeCP2）功能异常与雷特综合征相关，雷特综合征是女性认知障碍最常见的病因之一。MeCP2是一种内在无序蛋白（IDP），这使得对其进行实验表征具有挑战性。目前在任何数据库中都没有全长MeCP2的结构，仅其MBD结构域的结构已被解析。我们利用该结构通过从头建模完成蛋白质的其余部分，构建了MeCP2的全长模型。通过结合全原子模拟和粗粒度模拟，我们表征了其结构和动力学，以及在没有蛋白质其余部分的情况下ID和转录抑制结构域（TRD）结构域所采样的构象空间。目前的工作是对全长蛋白质的首次计算研究。在粗粒度模拟中采样到两种主要构象：一种类似于在全原子力场中观察到的球状结构和一种双球状构象。我们的全原子模型与现有的实验数据高度吻合，预测氨基酸W104被掩埋，氨基酸R111和R133可接触溶剂，α-螺旋含量为4.1%，而实验测得的为4%。最后，我们将AlphaFold预测的模型与我们的Modeller模型进行了比较。该模型在水中不稳定并发生了进一步折叠。总之，这些模拟提供了全长MeCP2详细的（可能不完整）构象集合，与实验数据兼容，可作为进一步研究的基础，例如对该蛋白质的突变体或其与生物伴侣相互作用的研究。
