Computational Biology and Clinical Informatics, Baker Institute, Melbourne, Victoria 3004, Australia.
Structural Biology and Bioinformatics, Department of Biochemistry and Molecular Biology, Bio21 Institute, University of Melbourne, Parkville, VIC, 3052, Australia.
Nucleic Acids Res. 2020 Jul 2;48(W1):W147-W153. doi: 10.1093/nar/gkaa416.
Significant efforts have been invested into understanding and predicting the molecular consequences of mutations in protein coding regions, however nearly all approaches have been developed using globular, soluble proteins. These methods have been shown to poorly translate to studying the effects of mutations in membrane proteins. To fill this gap, here we report, mCSM-membrane, a user-friendly web server that can be used to analyse the impacts of mutations on membrane protein stability and the likelihood of them being disease associated. mCSM-membrane derives from our well-established mutation modelling approach that uses graph-based signatures to model protein geometry and physicochemical properties for supervised learning. Our stability predictor achieved correlations of up to 0.72 and 0.67 (on cross validation and blind tests, respectively), while our pathogenicity predictor achieved a Matthew's Correlation Coefficient (MCC) of up to 0.77 and 0.73, outperforming previously described methods in both predicting changes in stability and in identifying pathogenic variants. mCSM-membrane will be an invaluable and dedicated resource for investigating the effects of single-point mutations on membrane proteins through a freely available, user friendly web server at http://biosig.unimelb.edu.au/mcsm_membrane.
尽管人们已经投入了大量精力来理解和预测蛋白质编码区域突变的分子后果，但几乎所有方法都是针对球状可溶性蛋白质开发的。这些方法在研究膜蛋白突变的影响时效果不佳。为了填补这一空白，我们在这里报告了 mCSM-membrane，这是一个用户友好的网络服务器，可用于分析突变对膜蛋白稳定性的影响，以及它们是否与疾病相关的可能性。mCSM-membrane 源自我们成熟的突变建模方法，该方法使用基于图的特征来模拟蛋白质的几何形状和物理化学特性，以便进行监督学习。我们的稳定性预测器在交叉验证和盲测中的相关性分别高达 0.72 和 0.67，而我们的致病性预测器的马修斯相关系数 (MCC) 高达 0.77 和 0.73，在预测稳定性变化和识别致病性变体方面均优于以前描述的方法。mCSM-membrane 将通过免费的、用户友好的网络服务器 http://biosig.unimelb.edu.au/mcsm_membrane，成为研究单点突变对膜蛋白影响的宝贵且专用资源。
