Predicting the Conformational Variability of Abl Tyrosine Kinase using Molecular Dynamics Simulations and Markov State Models

Journal of Chemical Theory and Computation
Yilin MengBenoît Roux

Abstract

Understanding protein conformational variability remains a challenge in drug discovery. The issue arises in protein kinases, whose multiple conformational states can affect the binding of small-molecule inhibitors. To overcome this challenge, we propose a comprehensive computational framework based on Markov state models (MSMs). Our framework integrates the information from explicit-solvent molecular dynamics simulations to accurately rank-order the accessible conformational variants of a target protein. We tested the methodology using Abl kinase with a reference and blind-test set. Only half of the Abl conformational variants discovered by our approach are present in the disclosed X-ray structures. The approach successfully identified a protein conformational state not previously observed in public structures but evident in a retrospective analysis of Lilly in-house structures: the X-ray structure of Abl with WHI-P154. Using a MSM-derived model, the free energy landscape and kinetic profile of Abl was analyzed in detail highlighting opportunities for targeting the unique metastable states.

References

Jun 1, 1994·Journal of Molecular Graphics·J SchlitterP Krüger
Oct 25, 2000·Protein Science : a Publication of the Protein Society·A FiserA Sali
Dec 10, 2002·Science·G ManningS Sudarsanam
Mar 26, 2003·Cell·Oliver HantschelGiulio Superti-Furga
Mar 26, 2003·Cell·Bhushan NagarJohn Kuriyan
Dec 17, 2004·Nature·Brian K Shoichet
May 4, 2005·Proceedings of the National Academy of Sciences of the United States of America·Hyung-June Woo, Benoît Roux
Dec 24, 2005·Angewandte Chemie·Martin VogtherrHarald Schwalbe
May 6, 2006·Current Opinion in Chemical Biology·Sutapa GhoshZiwei Huang
Sep 29, 2006·Journal of Medicinal Chemistry·Andrew R LeachCatherine E Peishoff
Dec 14, 2006·Acta Crystallographica. Section D, Biological Crystallography·Sandra W Cowan-JacobPaul W Manley
Aug 19, 2007·Proceedings of the National Academy of Sciences of the United States of America·José D Faraldo-Gómez, Benoît Roux
Feb 23, 2008·The Journal of Physical Chemistry. B·Albert C PanBenoît Roux
Apr 5, 2008·Journal of Medicinal Chemistry·Jeffrey J SutherlandMichal Vieth
Apr 16, 2008·Annual Review of Biochemistry·Rhiju Das, David Baker
Aug 22, 2008·The Journal of Chemical Physics·Albert C Pan, Benoît Roux
Dec 26, 2008·Proceedings of the National Academy of Sciences of the United States of America·Yibing ShanDavid E Shaw
May 5, 2009·Methods : a Companion to Methods in Enzymology·Gregory R BowmanVijay S Pande
Oct 2, 2009·The Journal of Chemical Physics·Gregory R BowmanVijay S Pande
Jan 15, 2010·Nature·Jianming ZhangNathanael S Gray
Jun 24, 2010·Methods : a Companion to Methods in Enzymology·Vijay S PandeGregory R Bowman
Nov 10, 2010·Biochemistry·Michael J KeiserBrian K Shoichet
May 10, 2011·The Journal of Chemical Physics·Jan-Hendrik PrinzFrank Noé
May 17, 2011·Journal of Chemical Information and Modeling·Cristiano R W GuimarãesLeonard Buckbinder
Jun 8, 2011·Proceedings of the National Academy of Sciences of the United States of America·Ignasi BuchGianni De Fabritiis
Jan 28, 2012·Journal of the American Chemical Society·Silvia LoveraFrancesco L Gervasio
Jan 15, 2013·The Journal of Biological Chemistry·Shoghag PanjarianThomas E Smithgall
Feb 1, 2013·Bioinformatics·Bryce Cronkite-Ratcliff, Vijay Pande
Sep 1, 2008·Expert Opinion on Drug Discovery·Darren Vs Green
Jan 1, 2010·Journal of Chemical Theory and Computation·Gregory R BowmanVijay S Pande
Jun 12, 2013·Journal of Chemical Theory and Computation·Christian R Schwantes, Vijay S Pande
Jun 25, 2013·Journal of Chemical Theory and Computation·James C GumbartChristophe Chipot
Jul 5, 2013·The Journal of Chemical Physics·Guillermo Pérez-HernándezFrank Noé
Oct 10, 2013·Journal of Molecular Biology·Yilin Meng, Benoît Roux
Mar 4, 2014·Nature Communications·Diwakar ShuklaVijay S Pande
Mar 29, 2014·Expert Opinion on Investigational Drugs·Morena FasanoFloriana Morgillo
Sep 10, 2014·Current Protocols in Bioinformatics·Benjamin Webb, Andrej Sali
Sep 15, 2014·Nature Structural & Molecular Biology·Roman V AgafonovDorothee Kern
Dec 31, 2014·The Journal of Physical Chemistry. B·Yilin MengBenoît Roux

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Citations

Nov 21, 2019·Chemistry : a European Journal·Stefano A Serapian, Giorgio Colombo
Jun 21, 2019·PLoS Computational Biology·Ruth NussinovHyunbum Jang
Jul 26, 2019·Physical Chemistry Chemical Physics : PCCP·Guido Todde, Ran Friedman
Jan 24, 2020·Frontiers in Chemistry·Zarko GagicKatarina Nikolic
Dec 20, 2019·The AAPS Journal·Naga Rajiv LakkanigaHong-Yu Li
Nov 6, 2020·Journal of Chemical Theory and Computation·Fabian PaulBenoît Roux
Sep 4, 2019·Journal of the American Chemical Society·Cheng-Chieh TsaiJana Shen
Nov 13, 2020·Journal of Chemical Information and Modeling·Jordi Juárez-JiménezJulien Michel
Nov 21, 2018·Journal of Chemical Information and Modeling·Jagna WitekSereina Riniker
Jul 25, 2019·Journal of Chemical Information and Modeling·Athina MeletiouCharles Laughton
Jan 31, 2020·Journal of Chemical Theory and Computation·Fabian PaulBenoît Roux
Oct 15, 2021·Journal of Chemical Theory and Computation·Baswanth Oruganti, Ran Friedman

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