Thermodynamics of camphor migration in cytochrome P450cam by atomistic simulations

Abstract Understanding the mechanisms of ligand binding to enzymes is of paramount importance for the design of new drugs. Here, we report on the use of a novel biased molecular dynamics (MD) methodology to study the mechanism of camphor binding to cytochrome P450cam. Microsecond-long MD simulations...

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Autores principales:	J. Rydzewski, W. Nowak
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/a60ad82258bf43eeb4e33c77163da74a
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spelling	oai:doaj.org-article:a60ad82258bf43eeb4e33c77163da74a2021-12-02T15:05:10ZThermodynamics of camphor migration in cytochrome P450cam by atomistic simulations10.1038/s41598-017-07993-02045-2322https://doaj.org/article/a60ad82258bf43eeb4e33c77163da74a2017-08-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-07993-0https://doaj.org/toc/2045-2322Abstract Understanding the mechanisms of ligand binding to enzymes is of paramount importance for the design of new drugs. Here, we report on the use of a novel biased molecular dynamics (MD) methodology to study the mechanism of camphor binding to cytochrome P450cam. Microsecond-long MD simulations allowed us to observe reaction coordinates characterizing ligand diffusion from the active site of cytochrome P450cam to solvent via three egress routes. These atomistic simulations were used to estimate thermodynamic quantities along the reaction coordinates and indicate diverse binding configurations. The results suggest that the diffusion of camphor along the pathway near the substrate recognition site (SRS) is thermodynamically preferred. In addition, we show that the diffusion near the SRS is triggered by a transition from a heterogeneous collection of closed ligand-bound conformers to the basin comprising the open conformations of cytochrome P450cam. The conformational change accompanying this switch is characterized by the retraction of the F and G helices and the disorder of the B′ helix. These results are corroborated by experimental studies and provide detailed insight into ligand binding and conformational behavior of the cytochrome family. The presented methodology is general and can be applied to other ligand-protein systems.J. RydzewskiW. NowakNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-10 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q J. Rydzewski W. Nowak Thermodynamics of camphor migration in cytochrome P450cam by atomistic simulations
description	Abstract Understanding the mechanisms of ligand binding to enzymes is of paramount importance for the design of new drugs. Here, we report on the use of a novel biased molecular dynamics (MD) methodology to study the mechanism of camphor binding to cytochrome P450cam. Microsecond-long MD simulations allowed us to observe reaction coordinates characterizing ligand diffusion from the active site of cytochrome P450cam to solvent via three egress routes. These atomistic simulations were used to estimate thermodynamic quantities along the reaction coordinates and indicate diverse binding configurations. The results suggest that the diffusion of camphor along the pathway near the substrate recognition site (SRS) is thermodynamically preferred. In addition, we show that the diffusion near the SRS is triggered by a transition from a heterogeneous collection of closed ligand-bound conformers to the basin comprising the open conformations of cytochrome P450cam. The conformational change accompanying this switch is characterized by the retraction of the F and G helices and the disorder of the B′ helix. These results are corroborated by experimental studies and provide detailed insight into ligand binding and conformational behavior of the cytochrome family. The presented methodology is general and can be applied to other ligand-protein systems.
format	article
author	J. Rydzewski W. Nowak
author_facet	J. Rydzewski W. Nowak
author_sort	J. Rydzewski
title	Thermodynamics of camphor migration in cytochrome P450cam by atomistic simulations
title_short	Thermodynamics of camphor migration in cytochrome P450cam by atomistic simulations
title_full	Thermodynamics of camphor migration in cytochrome P450cam by atomistic simulations
title_fullStr	Thermodynamics of camphor migration in cytochrome P450cam by atomistic simulations
title_full_unstemmed	Thermodynamics of camphor migration in cytochrome P450cam by atomistic simulations
title_sort	thermodynamics of camphor migration in cytochrome p450cam by atomistic simulations
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/a60ad82258bf43eeb4e33c77163da74a
work_keys_str_mv	AT jrydzewski thermodynamicsofcamphormigrationincytochromep450cambyatomisticsimulations AT wnowak thermodynamicsofcamphormigrationincytochromep450cambyatomisticsimulations
_version_	1718388912379920384

Thermodynamics of camphor migration in cytochrome P450cam by atomistic simulations

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