Predicting The Effects Of Missense Mutation On Protein-Nucleic Acid Interaction

Protein-nucleic acid interactions are involved in many important cellular life activities,such as transcription,replication,recombination,protein synthesis,and regulation of gene expression.When sequence variants that can alter the protein-nucleic acid interactions occur in these nucleic acid-binding proteins may cause significant perturbations or complete abolishment of function,which may lead to the occurrence of disease or cancer.Understanding the mechanism of impacts of variants on protein-nucleic acid interactions has become a persistent need.To address this demand,we introduced two new calculation methods,PremPDI and PremPRI,which can predict the effect of a single missense mutation in a protein on protein-DNA and protein-RNA interactions,respectively,and calculate the quantitative binding affinity change.Both PremPDI and PremPRI methods are based on molecular mechanical force fields and fast side-chain optimization algorithms,and use multiple sequence and structure features to construct multiple linear regression score functions.The parameters of PremPDI were optimized on experimental sets of 219 mutations from 49 protein-DNA complexes,while the parameters of PremPRI were optimized on experimental sets of 248 mutations from 50 protein-RNA complexes.Both PremPDI and PremPRI have achieved good agreement between the experimental and predicted binding affinity change with Pearson correlation coefficients of 0.71 and 0.72 and the corresponding root mean square errors of 0.86 kcal mol-1 and 0.76 kcal mol-1,respectively.PremPDI and PremPRI servers can map mutations on wild-type complexes,calculate changes in corresponding binding affinities,determine the deleterious effects of mutations,and generate a downloadable structural model of mutant complexes.PremPDI and PremPRI can be used for many tasks,such as finding functionally important variants,understanding the molecular mechanisms underlying the effects,and designing new inhibitors of protein-nucleic acid interactions.PremPDI and PremPRI web servers are available from https://lilab.jysw.suda.edu.cn/research/PremPDI/and https://lilab.jysw.suda.edu.cn/research/PremPRI/respectively.