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Importance of the Force Field Choice in Capturing Functionally Relevant Dynamics in the von Willebrand Factor

[Image: see text] Whether recent updates and new releases of atomistic force fields can model the structural and dynamical properties of proteins containing both folded and partially disordered domains is still unclear. To address this fundamental question, we tested eight recently released force fi...

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Autores principales: Kuzmanic, Antonija, Pritchard, Ruth B., Hansen, D. Flemming, Gervasio, Francesco L.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Chemical Society 2019
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6475856/
https://www.ncbi.nlm.nih.gov/pubmed/30933516
http://dx.doi.org/10.1021/acs.jpclett.9b00517
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author Kuzmanic, Antonija
Pritchard, Ruth B.
Hansen, D. Flemming
Gervasio, Francesco L.
author_facet Kuzmanic, Antonija
Pritchard, Ruth B.
Hansen, D. Flemming
Gervasio, Francesco L.
author_sort Kuzmanic, Antonija
collection PubMed
description [Image: see text] Whether recent updates and new releases of atomistic force fields can model the structural and dynamical properties of proteins containing both folded and partially disordered domains is still unclear. To address this fundamental question, we tested eight recently released force fields against our set of nuclear magnetic resonance (NMR) observables for a complex and medically relevant system, the major factor VIII binding region on the von Willebrand factor. This biomedically important region comprises both a folded and a partially structured domain. By using an enhanced sampling technique (temperature replica-exchange molecular dynamics simulations), we find that some force fields indeed rise to the challenge and capture the structural and dynamical features of the NMR ensemble and, therefore, are the appropriate choice for simulations of proteins with partially structured domains. What is more, we show that only such force fields can qualitatively capture the effects of a pathogenic mutation on the structural ensemble.
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spelling pubmed-64758562019-04-23 Importance of the Force Field Choice in Capturing Functionally Relevant Dynamics in the von Willebrand Factor Kuzmanic, Antonija Pritchard, Ruth B. Hansen, D. Flemming Gervasio, Francesco L. J Phys Chem Lett [Image: see text] Whether recent updates and new releases of atomistic force fields can model the structural and dynamical properties of proteins containing both folded and partially disordered domains is still unclear. To address this fundamental question, we tested eight recently released force fields against our set of nuclear magnetic resonance (NMR) observables for a complex and medically relevant system, the major factor VIII binding region on the von Willebrand factor. This biomedically important region comprises both a folded and a partially structured domain. By using an enhanced sampling technique (temperature replica-exchange molecular dynamics simulations), we find that some force fields indeed rise to the challenge and capture the structural and dynamical features of the NMR ensemble and, therefore, are the appropriate choice for simulations of proteins with partially structured domains. What is more, we show that only such force fields can qualitatively capture the effects of a pathogenic mutation on the structural ensemble. American Chemical Society 2019-04-01 2019-04-18 /pmc/articles/PMC6475856/ /pubmed/30933516 http://dx.doi.org/10.1021/acs.jpclett.9b00517 Text en Copyright © 2019 American Chemical Society This is an open access article published under a Creative Commons Attribution (CC-BY) License (http://pubs.acs.org/page/policy/authorchoice_ccby_termsofuse.html) , which permits unrestricted use, distribution and reproduction in any medium, provided the author and source are cited.
spellingShingle Kuzmanic, Antonija
Pritchard, Ruth B.
Hansen, D. Flemming
Gervasio, Francesco L.
Importance of the Force Field Choice in Capturing Functionally Relevant Dynamics in the von Willebrand Factor
title Importance of the Force Field Choice in Capturing Functionally Relevant Dynamics in the von Willebrand Factor
title_full Importance of the Force Field Choice in Capturing Functionally Relevant Dynamics in the von Willebrand Factor
title_fullStr Importance of the Force Field Choice in Capturing Functionally Relevant Dynamics in the von Willebrand Factor
title_full_unstemmed Importance of the Force Field Choice in Capturing Functionally Relevant Dynamics in the von Willebrand Factor
title_short Importance of the Force Field Choice in Capturing Functionally Relevant Dynamics in the von Willebrand Factor
title_sort importance of the force field choice in capturing functionally relevant dynamics in the von willebrand factor
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6475856/
https://www.ncbi.nlm.nih.gov/pubmed/30933516
http://dx.doi.org/10.1021/acs.jpclett.9b00517
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