A kinetic model of trp-cage folding from multiple biased molecular dynamics simulations.

Trp-cage is a designed 20-residue polypeptide that, in spite of its size, shares several features with larger globular proteins.Although the system has been intensively investigated experimentally and theoretically, its folding mechanism is not yet fully understood. Indeed, some experiments suggest...

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Autores principales:	Fabrizio Marinelli, Fabio Pietrucci, Alessandro Laio, Stefano Piana
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2009
Materias:	Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/f019af8a3ecf48a1888459ac6c17f978
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spelling	oai:doaj.org-article:f019af8a3ecf48a1888459ac6c17f9782021-11-25T05:42:15ZA kinetic model of trp-cage folding from multiple biased molecular dynamics simulations.1553-734X1553-735810.1371/journal.pcbi.1000452https://doaj.org/article/f019af8a3ecf48a1888459ac6c17f9782009-08-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/19662155/pdf/?tool=EBIhttps://doaj.org/toc/1553-734Xhttps://doaj.org/toc/1553-7358Trp-cage is a designed 20-residue polypeptide that, in spite of its size, shares several features with larger globular proteins.Although the system has been intensively investigated experimentally and theoretically, its folding mechanism is not yet fully understood. Indeed, some experiments suggest a two-state behavior, while others point to the presence of intermediates. In this work we show that the results of a bias-exchange metadynamics simulation can be used for constructing a detailed thermodynamic and kinetic model of the system. The model, although constructed from a biased simulation, has a quality similar to those extracted from the analysis of long unbiased molecular dynamics trajectories. This is demonstrated by a careful benchmark of the approach on a smaller system, the solvated Ace-Ala3-Nme peptide. For theTrp-cage folding, the model predicts that the relaxation time of 3100 ns observed experimentally is due to the presence of a compact molten globule-like conformation. This state has an occupancy of only 3% at 300 K, but acts as a kinetic trap.Instead, non-compact structures relax to the folded state on the sub-microsecond timescale. The model also predicts the presence of a state at Calpha-RMSD of 4.4 A from the NMR structure in which the Trp strongly interacts with Pro12. This state can explain the abnormal temperature dependence of the Pro12-delta3 and Gly11-alpha3 chemical shifts. The structures of the two most stable misfolded intermediates are in agreement with NMR experiments on the unfolded protein. Our work shows that, using biased molecular dynamics trajectories, it is possible to construct a model describing in detail the Trp-cage folding kinetics and thermodynamics in agreement with experimental data.Fabrizio MarinelliFabio PietrucciAlessandro LaioStefano PianaPublic Library of Science (PLoS)articleBiology (General)QH301-705.5ENPLoS Computational Biology, Vol 5, Iss 8, p e1000452 (2009)
institution	DOAJ
collection	DOAJ
language	EN
topic	Biology (General) QH301-705.5
spellingShingle	Biology (General) QH301-705.5 Fabrizio Marinelli Fabio Pietrucci Alessandro Laio Stefano Piana A kinetic model of trp-cage folding from multiple biased molecular dynamics simulations.
description	Trp-cage is a designed 20-residue polypeptide that, in spite of its size, shares several features with larger globular proteins.Although the system has been intensively investigated experimentally and theoretically, its folding mechanism is not yet fully understood. Indeed, some experiments suggest a two-state behavior, while others point to the presence of intermediates. In this work we show that the results of a bias-exchange metadynamics simulation can be used for constructing a detailed thermodynamic and kinetic model of the system. The model, although constructed from a biased simulation, has a quality similar to those extracted from the analysis of long unbiased molecular dynamics trajectories. This is demonstrated by a careful benchmark of the approach on a smaller system, the solvated Ace-Ala3-Nme peptide. For theTrp-cage folding, the model predicts that the relaxation time of 3100 ns observed experimentally is due to the presence of a compact molten globule-like conformation. This state has an occupancy of only 3% at 300 K, but acts as a kinetic trap.Instead, non-compact structures relax to the folded state on the sub-microsecond timescale. The model also predicts the presence of a state at Calpha-RMSD of 4.4 A from the NMR structure in which the Trp strongly interacts with Pro12. This state can explain the abnormal temperature dependence of the Pro12-delta3 and Gly11-alpha3 chemical shifts. The structures of the two most stable misfolded intermediates are in agreement with NMR experiments on the unfolded protein. Our work shows that, using biased molecular dynamics trajectories, it is possible to construct a model describing in detail the Trp-cage folding kinetics and thermodynamics in agreement with experimental data.
format	article
author	Fabrizio Marinelli Fabio Pietrucci Alessandro Laio Stefano Piana
author_facet	Fabrizio Marinelli Fabio Pietrucci Alessandro Laio Stefano Piana
author_sort	Fabrizio Marinelli
title	A kinetic model of trp-cage folding from multiple biased molecular dynamics simulations.
title_short	A kinetic model of trp-cage folding from multiple biased molecular dynamics simulations.
title_full	A kinetic model of trp-cage folding from multiple biased molecular dynamics simulations.
title_fullStr	A kinetic model of trp-cage folding from multiple biased molecular dynamics simulations.
title_full_unstemmed	A kinetic model of trp-cage folding from multiple biased molecular dynamics simulations.
title_sort	kinetic model of trp-cage folding from multiple biased molecular dynamics simulations.
publisher	Public Library of Science (PLoS)
publishDate	2009
url	https://doaj.org/article/f019af8a3ecf48a1888459ac6c17f978
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A kinetic model of trp-cage folding from multiple biased molecular dynamics simulations.

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