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Toward Developing Intuitive Rules for Protein Variant Effect Prediction Using Deep Mutational Scanning Data

[Image: see text] Protein structure and function can be severely altered by even a single amino acid mutation. Predictions of mutational effects using extensive artificial intelligence (AI)-based models, although accurate, remain as enigmatic as the experimental observations in terms of improving in...

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Detalles Bibliográficos
Autores principales: Sruthi, Cheloor Kovilakam, Balaram, Hemalatha, Prakash, Meher K.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Chemical Society 2020
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7689672/
https://www.ncbi.nlm.nih.gov/pubmed/33251402
http://dx.doi.org/10.1021/acsomega.0c02402
Descripción
Sumario:[Image: see text] Protein structure and function can be severely altered by even a single amino acid mutation. Predictions of mutational effects using extensive artificial intelligence (AI)-based models, although accurate, remain as enigmatic as the experimental observations in terms of improving intuitions about the contributions of various factors. Inspired by Lipinski’s rules for drug-likeness, we devise simple thresholding criteria on five different descriptors such as conservation, which have so far been limited to qualitative interpretations such as high conservation implies high mutational effect. We analyze systematic deep mutational scanning data of all possible single amino acid substitutions on seven proteins (25153 mutations) to first define these thresholds and then to evaluate the scope and limits of the predictions. At this stage, the approach allows us to comment easily and with a low error rate on the subset of mutations classified as neutral or deleterious by all of the descriptors. We hope that complementary to the accurate AI predictions, these thresholding rules or their subsequent modifications will serve the purpose of codifying the knowledge about the effects of mutations.