Systematic comparison and prediction of the effects of missense mutations on protein-DNA and protein-RNA interactions

Yao Jiang, Hui-Fang Liu and Rong Liu

PLOS Computational Biology, 2021, vol. 17, issue 4, 1-22

Abstract: The binding affinities of protein-nucleic acid interactions could be altered due to missense mutations occurring in DNA- or RNA-binding proteins, therefore resulting in various diseases. Unfortunately, a systematic comparison and prediction of the effects of mutations on protein-DNA and protein-RNA interactions (these two mutation classes are termed MPDs and MPRs, respectively) is still lacking. Here, we demonstrated that these two classes of mutations could generate similar or different tendencies for binding free energy changes in terms of the properties of mutated residues. We then developed regression algorithms separately for MPDs and MPRs by introducing novel geometric partition-based energy features and interface-based structural features. Through feature selection and ensemble learning, similar computational frameworks that integrated energy- and nonenergy-based models were established to estimate the binding affinity changes resulting from MPDs and MPRs, but the selected features for the final models were different and therefore reflected the specificity of these two mutation classes. Furthermore, the proposed methodology was extended to the identification of mutations that significantly decreased the binding affinities. Extensive validations indicated that our algorithm generally performed better than the state-of-the-art methods on both the regression and classification tasks. The webserver and software are freely available at http://liulab.hzau.edu.cn/PEMPNI and https://github.com/hzau-liulab/PEMPNI.Author summary: Protein-nucleic acid interactions play important roles in various cellular processes. Missense mutations occurring in DNA- or RNA-binding proteins (termed MPDs and MPRs, respectively) could change the binding affinities of these interactions. Previous studies have compared protein-DNA and protein-RNA interactions from multifaceted viewpoints, but less attention has been given to the similarities and specific differences between the effects of MPDs and MPRs and between the methodologies for predicting the affinity changes induced by the two mutation classes. Therefore, we systematically compared their impacts and demonstrated that MPDs and MPRs could have specific preferences for binding affinity changes. These observations motivated us to construct regression models separately for MPDs and MPRs by introducing novel energy and nonenergy descriptors. Although similar frameworks were developed to estimate these two categories of mutation effects, different descriptors were selected in the regression models and further revealed the specificity of mutation classes. The interplay between the energy and nonenergy modules effectively improved prediction performance. Our algorithm can also be adopted to disentangle mutations significantly decreasing binding affinities from other mutations.

Date: 2021
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Persistent link: https://EconPapers.repec.org/RePEc:plo:pcbi00:1008951

DOI: 10.1371/journal.pcbi.1008951

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