BindProfX: Assessing Mutation-Induced Binding Affinity Change by Protein Interface Profiles with Pseudo-Counts.

TitleBindProfX: Assessing Mutation-Induced Binding Affinity Change by Protein Interface Profiles with Pseudo-Counts.
Publication TypeJournal Article
Year of Publication2017
AuthorsXiong P, Zhang C, Zheng W, Zhang Y
JournalJ Mol Biol
Date Published2017 Feb 03
KeywordsAlgorithms, Amino Acid Sequence, Computational Biology, Models, Molecular, Mutation, Protein Conformation, Protein Engineering, Protein Interaction Maps, Proteins

Understanding how gene-level mutations affect the binding affinity of protein-protein interactions is a key issue of protein engineering. Due to the complexity of the problem, using physical force field to predict the mutation-induced binding free-energy change remains challenging. In this work, we present a renewed approach to calculate the impact of gene mutations on the binding affinity through the structure-based profiling of protein-protein interfaces, where the binding free-energy change (ΔΔG) is counted as the logarithm of relative probability of mutant amino acids over wild-type ones in the interface alignment matrix; three pseudo-counts are introduced to alleviate the limit of the current interface library. Compared with a previous profile score that was based on the log-odds likelihood calculation, the correlation between predicted and experimental ΔΔG of single-site mutations is increased in this approach from 0.33 to 0.68. The structure-based profile score is found complementary to the physical potentials, where a linear combination of the profile score with the FoldX potential could increase the ΔΔG correlation from 0.46 to 0.74. It is also shown that the profile score is robust for counting the coupling effect of multiple individual mutations. For the mutations involving more than two mutation sites where the correlation between FoldX and experimental data vanishes, the profile-based calculation retains a strong correlation with the experimental measurements.

Alternate JournalJ. Mol. Biol.
PubMed ID27899282