Predicting the impacts of mutations on protein-ligand binding affinity based on molecular dynamics simulations and machine learning methods

Computational and Structural Biotechnology Journal
Debby D WangHong Yan

Abstract

Mutation-induced variation of protein-ligand binding affinity is the key to many genetic diseases and the emergence of drug resistance, and therefore predicting such mutation impacts is of great importance. In this work, we aim to predict the mutation impacts on protein-ligand binding affinity using efficient structure-based, computational methods. Relying on consolidated databases of experimentally determined data we characterize the affinity change upon mutation based on a number of local geometrical features and monitor such feature differences upon mutation during molecular dynamics (MD) simulations. The differences are quantified according to average difference, trajectory-wise distance or time-vary differences. Machine-learning methods are employed to predict the mutation impacts using the resulting conventional or time-series features. Predictions based on estimation of energy and based on investigation of molecular descriptors were conducted as benchmarks. Our method (machine-learning techniques using time-series features) outperformed the benchmark methods, especially in terms of the balanced F1 score. Particularly, deep-learning models led to the best prediction performance with distinct improvements in balanced F1 sc...Continue Reading

References

Sep 12, 1995·Proceedings of the National Academy of Sciences of the United States of America·I DubchakS H Kim
Aug 24, 2000·Journal of Chemical Information and Computer Sciences·S C BasakB D Gute
Mar 29, 2001·Journal of Pharmaceutical and Biomedical Analysis·S Agatonovic-KustrinA P Yusof
Oct 17, 2002·Proceedings of the National Academy of Sciences of the United States of America·Tanja Kortemme, David Baker
Dec 28, 2002·Journal of Medicinal Chemistry·Ismael ZamoraAnna-Lena Ungell
Dec 19, 2003·Nucleic Acids Research·K Abdulla BavaAkinori Sarai
Mar 23, 2004·Journal of Chemical Information and Computer Sciences·Wei DengMark J Embrechts
Apr 6, 2004·Methods in Enzymology·Carol A RohlDavid Baker
Jul 21, 2004·Journal of Computational Chemistry·Eric F PettersenThomas E Ferrin
Oct 14, 2004·Journal of Computational Chemistry·John MonganJ Andrew McCammon
Jun 28, 2005·Nucleic Acids Research·John C GordonAlexey Onufriev
Dec 31, 2005·Nucleic Acids Research·M D Shaji KumarAkinori Sarai
Jan 4, 2012·Journal of Molecular Recognition : JMR·Rajesh GhaiBrett M Collins
Feb 7, 2012·Proceedings of the National Academy of Sciences of the United States of America·Yael PhillipGideon Schreiber
May 15, 2012·Journal of Chemical Theory and Computation·Andreas W GötzRoss C Walker
Nov 23, 2012·Current Pharmaceutical Design·Marharyta PetukhEmil Alexov
Jul 23, 2013·Journal of Molecular Biology·Shannon SteflEmil Alexov
Aug 6, 2013·Journal of Chemical Theory and Computation·Pengfei LiKenneth M Merz
Oct 5, 2013·Scientific Reports·Debby D WangVictor Lee
Feb 7, 2015·Current Opinion in Structural Biology·Tugba G KucukkalEmil Alexov
Apr 4, 2015·Expert Opinion on Drug Discovery·Samuel Genheden, Ulf Ryde
Sep 10, 2013·Journal of Chemical Theory and Computation·Romelia Salomon-FerrerRoss C Walker
Mar 11, 2016·Molecular BioSystems·Debby D WangHong Yan
Dec 4, 2016·Progress in Biophysics and Molecular Biology·Harry C JubbDavid B Ascher
Mar 1, 2017·Journal of Chemical Theory and Computation·Jin ZhangDavid van der Spoel
May 20, 2017·Nucleic Acids Research·Arun Prasad PanduranganTom L Blundell

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Methods Mentioned

BETA
feature extraction
X-ray

Software Mentioned

Rosetta
GBSA
PBSA
Platinum
Rosetta DDG _ monomer
mut
Abl
AMBER
MM
paacomp

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