De Baets Greet, Van Durme Joost, van der Kant Rob, Schymkowitz Joost, Rousseau Frederic
VIB Switch Laboratory, Department of Cellular and Molecular Medicine, Katholieke Universiteit Leuven, 3000 Leuven, Belgium and Vrije Universiteit Brussel, 1050 Brussels, Belgium.
VIB Switch Laboratory, Department of Cellular and Molecular Medicine, Katholieke Universiteit Leuven, 3000 Leuven, Belgium and.
Bioinformatics. 2015 Aug 1;31(15):2580-2. doi: 10.1093/bioinformatics/btv162. Epub 2015 Mar 19.
Protein aggregation is associated with a number of protein misfolding diseases and is a major concern for therapeutic proteins. Aggregation is caused by the presence of aggregation-prone regions (APRs) in the amino acid sequence of the protein. The lower the aggregation propensity of APRs and the better they are protected by native interactions within the folded structure of the protein, the more aggregation is prevented. Therefore, both the local thermodynamic stability of APRs in the native structure and their intrinsic aggregation propensity are a key parameter that needs to be optimized to prevent protein aggregation.
The Solubis method presented here automates the process of carefully selecting point mutations that minimize the intrinsic aggregation propensity while improving local protein stability.
蛋白质聚集与多种蛋白质错误折叠疾病相关，并且是治疗性蛋白质的一个主要问题。聚集是由蛋白质氨基酸序列中存在易于聚集的区域（APR）引起的。APR的聚集倾向越低，并且在蛋白质折叠结构内被天然相互作用保护得越好，则聚集被阻止得就越多。因此，天然结构中APR的局部热力学稳定性及其内在聚集倾向都是为防止蛋白质聚集而需要优化的关键参数。
本文提出的Solubis方法可自动完成仔细选择点突变的过程，这些点突变可在提高局部蛋白质稳定性的同时将内在聚集倾向降至最低。
