In silico functional dissection of saturation mutagenesis: Interpreting the relationship between phenotypes and changes in protein stability, interactions and activity

Scientific Reports
Douglas E V PiresDavid B Ascher

Abstract

Despite interest in associating polymorphisms with clinical or experimental phenotypes, functional interpretation of mutation data has lagged behind generation of data from modern high-throughput techniques and the accurate prediction of the molecular impact of a mutation remains a non-trivial task. We present here an integrated knowledge-driven computational workflow designed to evaluate the effects of experimental and disease missense mutations on protein structure and interactions. We exemplify its application with analyses of saturation mutagenesis of DBR1 and Gal4 and show that the experimental phenotypes for over 80% of the mutations correlate well with predicted effects of mutations on protein stability and RNA binding affinity. We also show that analysis of mutations in VHL using our workflow provides valuable insights into the effects of mutations, and their links to the risk of developing renal carcinoma. Taken together the analyses of the three examples demonstrate that structural bioinformatics tools, when applied in a systematic, integrated way, can rapidly analyse a given system to provide a powerful approach for predicting structural and functional effects of thousands of mutations in order to reveal molecular me...Continue Reading

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Citations

Nov 9, 2016·International Journal of Breast Cancer·T PesaranA Elliott
May 20, 2017·Nucleic Acids Research·Arun Prasad PanduranganTom L Blundell
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Apr 26, 2018·American Journal of Respiratory and Critical Care Medicine·Malancha KarmakarDavid B Ascher
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Apr 7, 2017·Nucleic Acids Research·Douglas E V Pires, David B Ascher
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Methods Mentioned

BETA
in silico methods
dissection
X-ray

Software Mentioned

Random
Weka
Symphony
Crescendo
Verify3D
Modeller
SDM
DUET
MacroModel
mCSM

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