KRAS(G12C)–AMG 510 interaction dynamics revealed by all-atom molecular dynamics simulations

Abstract The first KRAS(G12C) targeting inhibitor in clinical development, AMG 510, has shown promising antitumor activity in clinical trials. On the molecular level, however, the interaction dynamics of this covalently bound drug–protein complex has been undetermined. Here, we disclose the interact...

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Autor principal: Tatu Pantsar
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Publicado: Nature Portfolio 2020
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spelling oai:doaj.org-article:5b1c9467f57d40f7a97ffe6051ad08bb2021-12-02T16:26:22ZKRAS(G12C)–AMG 510 interaction dynamics revealed by all-atom molecular dynamics simulations10.1038/s41598-020-68950-y2045-2322https://doaj.org/article/5b1c9467f57d40f7a97ffe6051ad08bb2020-07-01T00:00:00Zhttps://doi.org/10.1038/s41598-020-68950-yhttps://doaj.org/toc/2045-2322Abstract The first KRAS(G12C) targeting inhibitor in clinical development, AMG 510, has shown promising antitumor activity in clinical trials. On the molecular level, however, the interaction dynamics of this covalently bound drug–protein complex has been undetermined. Here, we disclose the interaction dynamics of the KRAS(G12C)–AMG 510 complex by long timescale all-atom molecular dynamics (MD) simulations (total of 75 μs). Moreover, we investigated the influence of the recently reported post-translational modification (PTM) of KRAS’ N-terminus, removal of initiator methionine (iMet1) with acetylation of Thr2, to this complex. Our results demonstrate that AMG 510 does not entrap KRAS into a single conformation, as one would expect based on the crystal structure, but rather into an ensemble of conformations. AMG 510 binding is extremely stable regardless of highly dynamic interface of KRAS’ switches. Overall, KRAS(G12C)–AMG 510 complex partially mimic the native dynamics of GDP bound KRAS; however, AMG 510 stabilizes the α3-helix region. N-terminally modified KRAS displays similar interaction dynamics with AMG 510 as when Met1 is present, but this PTM appears to stabilize β2–β3-loop. These results provide novel conformational insights on the molecular level to KRAS(G12C)–AMG 510 interactions and dynamics, providing new perspectives to RAS related drug discovery.Tatu PantsarNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 10, Iss 1, Pp 1-9 (2020)
institution DOAJ
collection DOAJ
language EN
topic Medicine
R
Science
Q
spellingShingle Medicine
R
Science
Q
Tatu Pantsar
KRAS(G12C)–AMG 510 interaction dynamics revealed by all-atom molecular dynamics simulations
description Abstract The first KRAS(G12C) targeting inhibitor in clinical development, AMG 510, has shown promising antitumor activity in clinical trials. On the molecular level, however, the interaction dynamics of this covalently bound drug–protein complex has been undetermined. Here, we disclose the interaction dynamics of the KRAS(G12C)–AMG 510 complex by long timescale all-atom molecular dynamics (MD) simulations (total of 75 μs). Moreover, we investigated the influence of the recently reported post-translational modification (PTM) of KRAS’ N-terminus, removal of initiator methionine (iMet1) with acetylation of Thr2, to this complex. Our results demonstrate that AMG 510 does not entrap KRAS into a single conformation, as one would expect based on the crystal structure, but rather into an ensemble of conformations. AMG 510 binding is extremely stable regardless of highly dynamic interface of KRAS’ switches. Overall, KRAS(G12C)–AMG 510 complex partially mimic the native dynamics of GDP bound KRAS; however, AMG 510 stabilizes the α3-helix region. N-terminally modified KRAS displays similar interaction dynamics with AMG 510 as when Met1 is present, but this PTM appears to stabilize β2–β3-loop. These results provide novel conformational insights on the molecular level to KRAS(G12C)–AMG 510 interactions and dynamics, providing new perspectives to RAS related drug discovery.
format article
author Tatu Pantsar
author_facet Tatu Pantsar
author_sort Tatu Pantsar
title KRAS(G12C)–AMG 510 interaction dynamics revealed by all-atom molecular dynamics simulations
title_short KRAS(G12C)–AMG 510 interaction dynamics revealed by all-atom molecular dynamics simulations
title_full KRAS(G12C)–AMG 510 interaction dynamics revealed by all-atom molecular dynamics simulations
title_fullStr KRAS(G12C)–AMG 510 interaction dynamics revealed by all-atom molecular dynamics simulations
title_full_unstemmed KRAS(G12C)–AMG 510 interaction dynamics revealed by all-atom molecular dynamics simulations
title_sort kras(g12c)–amg 510 interaction dynamics revealed by all-atom molecular dynamics simulations
publisher Nature Portfolio
publishDate 2020
url https://doaj.org/article/5b1c9467f57d40f7a97ffe6051ad08bb
work_keys_str_mv AT tatupantsar krasg12camg510interactiondynamicsrevealedbyallatommoleculardynamicssimulations
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