Biochemistry and Pharmacology - Research Publications
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ItemStructure-guided machine learning prediction of drug resistance mutations in Abelson 1 kinase(ELSEVIER, 2021)Kinases play crucial roles in cellular signalling and biological processes with their dysregulation associated with diseases, including cancers. Kinase inhibitors, most notably those targeting ABeLson 1 (ABL1) kinase in chronic myeloid leukemia, have had a significant impact on cancer survival, yet emergence of resistance mutations can reduce their effectiveness, leading to therapeutic failure. Limited effort, however, has been devoted to developing tools to accurately identify ABL1 resistance mutations, as well as providing insights into their molecular mechanisms. Here we investigated the structural basis of ABL1 mutations modulating binding affinity of eight FDA-approved drugs. We found mutations impair affinity of type I and type II inhibitors differently and used this insight to developed a novel web-based diagnostic tool, SUSPECT-ABL, to pre-emptively predict resistance profiles and binding free-energy changes (ΔΔG) of all possible ABL1 mutations against inhibitors with different binding modes. Resistance mutations in ABL1 were successfully identified, achieving a Matthew's Correlation Coefficient of up to 0.73 and the resulting change in ligand binding affinity with a Pearson's correlation of up to 0.77, with performances consistent across non-redundant blind tests. Through an in silico saturation mutagenesis, our tool has identified possibly emerging resistance mutations, which offers opportunities for in vivo experimental validation. We believe SUSPECT-ABL will be an important tool not just for improving precision medicine efforts, but for facilitating the development of next-generation inhibitors that are less prone to resistance. We have made our tool freely available at http://biosig.unimelb.edu.au/suspect_abl/.
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ItemmmCSM-PPI: predicting the effects of multiple point mutations on protein-protein interactions(OXFORD UNIV PRESS, 2021-07-02)Protein-protein interactions play a crucial role in all cellular functions and biological processes and mutations leading to their disruption are enriched in many diseases. While a number of computational methods to assess the effects of variants on protein-protein binding affinity have been proposed, they are in general limited to the analysis of single point mutations and have been shown to perform poorly on independent test sets. Here, we present mmCSM-PPI, a scalable and effective machine learning model for accurately assessing changes in protein-protein binding affinity caused by single and multiple missense mutations. We expanded our well-established graph-based signatures in order to capture physicochemical and geometrical properties of multiple wild-type residue environments and integrated them with substitution scores and dynamics terms from normal mode analysis. mmCSM-PPI was able to achieve a Pearson's correlation of up to 0.75 (RMSE = 1.64 kcal/mol) under 10-fold cross-validation and 0.70 (RMSE = 2.06 kcal/mol) on a non-redundant blind test, outperforming existing methods. Our method is freely available as a user-friendly and easy-to-use web server and API at http://biosig.unimelb.edu.au/mmcsm_ppi.
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ItemDynaMut2: Assessing changes in stability and flexibility upon single and multiple point missense mutations(WILEY, 2021-01)Predicting the effect of missense variations on protein stability and dynamics is important for understanding their role in diseases, and the link between protein structure and function. Approaches to estimate these changes have been proposed, but most only consider single-point missense variants and a static state of the protein, with those that incorporate dynamics are computationally expensive. Here we present DynaMut2, a web server that combines Normal Mode Analysis (NMA) methods to capture protein motion and our graph-based signatures to represent the wildtype environment to investigate the effects of single and multiple point mutations on protein stability and dynamics. DynaMut2 was able to accurately predict the effects of missense mutations on protein stability, achieving Pearson's correlation of up to 0.72 (RMSE: 1.02 kcal/mol) on a single point and 0.64 (RMSE: 1.80 kcal/mol) on multiple-point missense mutations across 10-fold cross-validation and independent blind tests. For single-point mutations, DynaMut2 achieved comparable performance with other methods when predicting variations in Gibbs Free Energy (ΔΔG) and in melting temperature (ΔTm ). We anticipate our tool to be a valuable suite for the study of protein flexibility analysis and the study of the role of variants in disease. DynaMut2 is freely available as a web server and API at http://biosig.unimelb.edu.au/dynamut2.
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ItemmCSM-membrane: predicting the effects of mutations on transmembrane proteins.(Oxford University Press, 2020-07-02)Significant efforts have been invested into understanding and predicting the molecular consequences of mutations in protein coding regions, however nearly all approaches have been developed using globular, soluble proteins. These methods have been shown to poorly translate to studying the effects of mutations in membrane proteins. To fill this gap, here we report, mCSM-membrane, a user-friendly web server that can be used to analyse the impacts of mutations on membrane protein stability and the likelihood of them being disease associated. mCSM-membrane derives from our well-established mutation modelling approach that uses graph-based signatures to model protein geometry and physicochemical properties for supervised learning. Our stability predictor achieved correlations of up to 0.72 and 0.67 (on cross validation and blind tests, respectively), while our pathogenicity predictor achieved a Matthew's Correlation Coefficient (MCC) of up to 0.77 and 0.73, outperforming previously described methods in both predicting changes in stability and in identifying pathogenic variants. mCSM-membrane will be an invaluable and dedicated resource for investigating the effects of single-point mutations on membrane proteins through a freely available, user friendly web server at http://biosig.unimelb.edu.au/mcsm_membrane.