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
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2020
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/5b1c9467f57d40f7a97ffe6051ad08bb
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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
_version_	1718384053249376256

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

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