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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Main Authors: J. Rydzewski, W. Nowak
Format: Article
Language:English
Published: Nature Portfolio 2017-08-01
Series:Scientific Reports
Online Access:https://doi.org/10.1038/s41598-017-07993-0
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author J. Rydzewski
W. Nowak
author_facet J. Rydzewski
W. Nowak
author_sort J. Rydzewski
collection DOAJ
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.
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spelling doaj.art-a60ad82258bf43eeb4e33c77163da74a2022-12-21T23:38:19ZengNature PortfolioScientific Reports2045-23222017-08-017111010.1038/s41598-017-07993-0Thermodynamics of camphor migration in cytochrome P450cam by atomistic simulationsJ. Rydzewski0W. Nowak1Institute of Physics, Faculty of Physics, Astronomy and Informatics, Nicolaus Copernicus University, Grudziadzka 5Institute of Physics, Faculty of Physics, Astronomy and Informatics, Nicolaus Copernicus University, Grudziadzka 5Abstract 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.https://doi.org/10.1038/s41598-017-07993-0
spellingShingle J. Rydzewski
W. Nowak
Thermodynamics of camphor migration in cytochrome P450cam by atomistic simulations
Scientific Reports
title 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_short Thermodynamics of camphor migration in cytochrome P450cam by atomistic simulations
title_sort thermodynamics of camphor migration in cytochrome p450cam by atomistic simulations
url https://doi.org/10.1038/s41598-017-07993-0
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