Nguyen Thanh Binh, Myung Yoochan, de Sá Alex G C, Pires Douglas E V, Ascher David B
Computational Biology and Clinical Informatics, Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia.
NAR Genom Bioinform. 2021 Nov 17;3(4):lqab109. doi: 10.1093/nargab/lqab109. eCollection 2021 Dec.
While protein-nucleic acid interactions are pivotal for many crucial biological processes, limited experimental data has made the development of computational approaches to characterise these interactions a challenge. Consequently, most approaches to understand the effects of missense mutations on protein-nucleic acid affinity have focused on single-point mutations and have presented a limited performance on independent data sets. To overcome this, we have curated the largest dataset of experimentally measured effects of mutations on nucleic acid binding affinity to date, encompassing 856 single-point mutations and 141 multiple-point mutations across 155 experimentally solved complexes. This was used in combination with an optimized version of our graph-based signatures to develop mmCSM-NA (http://biosig.unimelb.edu.au/mmcsm_na), the first scalable method capable of quantitatively and accurately predicting the effects of multiple-point mutations on nucleic acid binding affinities. mmCSM-NA obtained a Pearson's correlation of up to 0.67 (RMSE of 1.06 Kcal/mol) on single-point mutations under cross-validation, and up to 0.65 on independent non-redundant datasets of multiple-point mutations (RMSE of 1.12 kcal/mol), outperforming similar tools. mmCSM-NA is freely available as an easy-to-use web-server and API. We believe it will be an invaluable tool to shed light on the role of mutations affecting protein-nucleic acid interactions in diseases.
虽然蛋白质与核酸的相互作用对许多关键生物过程至关重要，但有限的实验数据使得开发用于表征这些相互作用的计算方法成为一项挑战。因此，大多数理解错义突变对蛋白质 - 核酸亲和力影响的方法都集中在单点突变上，并且在独立数据集上表现有限。为了克服这一问题，我们精心整理了迄今为止最大的关于突变对核酸结合亲和力影响的实验测量数据集，涵盖了155个实验解析复合物中的856个单点突变和141个多点突变。这与我们基于图的特征的优化版本相结合，开发了mmCSM - NA（http://biosig.unimelb.edu.au/mmcsm_na），这是第一种能够定量准确预测多点突变对核酸结合亲和力影响的可扩展方法。mmCSM - NA在交叉验证下对单点突变的皮尔逊相关系数高达0.67（均方根误差为1.06千卡/摩尔），在多点突变的独立非冗余数据集上高达0.65（均方根误差为1.12千卡/摩尔），优于类似工具。mmCSM - NA可作为易于使用的网络服务器和应用程序编程接口免费获取。我们相信它将成为揭示影响蛋白质 - 核酸相互作用的突变在疾病中的作用的宝贵工具。
