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An Improved Strategy for Generating Forces in Steered Molecular Dynamics: The Mechanical Unfolding of Titin, e2lip3 and Ubiquitin

One of the applications of Molecular Dynamics (MD) simulations is to explore the energetic barriers to mechanical unfolding of proteins such as occurs in response to the mechanical pulling of single molecules in Atomic Force Microscopy (AFM) experiments. Although Steered Molecular Dynamics simulatio...

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Detalles Bibliográficos
Autores principales: Ho, Bosco K., Agard, David A.
Formato: Texto
Lenguaje:English
Publicado: Public Library of Science 2010
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2947501/
https://www.ncbi.nlm.nih.gov/pubmed/20927369
http://dx.doi.org/10.1371/journal.pone.0013068
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author Ho, Bosco K.
Agard, David A.
author_facet Ho, Bosco K.
Agard, David A.
author_sort Ho, Bosco K.
collection PubMed
description One of the applications of Molecular Dynamics (MD) simulations is to explore the energetic barriers to mechanical unfolding of proteins such as occurs in response to the mechanical pulling of single molecules in Atomic Force Microscopy (AFM) experiments. Although Steered Molecular Dynamics simulations have provided microscopic details of the unfolding process during the pulling, the simulated forces required for unfolding are typically far in excess of the measured values. To rectify this, we have developed the Pulsed Unconstrained Fluctuating Forces (PUFF) method, which induces constant-momentum motions by applying forces directly to the instantaneous velocity of selected atoms in a protein system. The driving forces are applied in pulses, which allows the system to relax between pulses, resulting in more accurate unfolding force estimations than in previous methods. In the cases of titin, ubiquitin and e2lip3, the PUFF trajectories produce force fluctuations that agree quantitatively with AFM experiments. Another useful property of PUFF is that simulations get trapped if the target momentum is too low, simplifying the discovery and analysis of unfolding intermediates.
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spelling pubmed-29475012010-10-06 An Improved Strategy for Generating Forces in Steered Molecular Dynamics: The Mechanical Unfolding of Titin, e2lip3 and Ubiquitin Ho, Bosco K. Agard, David A. PLoS One Research Article One of the applications of Molecular Dynamics (MD) simulations is to explore the energetic barriers to mechanical unfolding of proteins such as occurs in response to the mechanical pulling of single molecules in Atomic Force Microscopy (AFM) experiments. Although Steered Molecular Dynamics simulations have provided microscopic details of the unfolding process during the pulling, the simulated forces required for unfolding are typically far in excess of the measured values. To rectify this, we have developed the Pulsed Unconstrained Fluctuating Forces (PUFF) method, which induces constant-momentum motions by applying forces directly to the instantaneous velocity of selected atoms in a protein system. The driving forces are applied in pulses, which allows the system to relax between pulses, resulting in more accurate unfolding force estimations than in previous methods. In the cases of titin, ubiquitin and e2lip3, the PUFF trajectories produce force fluctuations that agree quantitatively with AFM experiments. Another useful property of PUFF is that simulations get trapped if the target momentum is too low, simplifying the discovery and analysis of unfolding intermediates. Public Library of Science 2010-09-29 /pmc/articles/PMC2947501/ /pubmed/20927369 http://dx.doi.org/10.1371/journal.pone.0013068 Text en Ho, Agard. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Ho, Bosco K.
Agard, David A.
An Improved Strategy for Generating Forces in Steered Molecular Dynamics: The Mechanical Unfolding of Titin, e2lip3 and Ubiquitin
title An Improved Strategy for Generating Forces in Steered Molecular Dynamics: The Mechanical Unfolding of Titin, e2lip3 and Ubiquitin
title_full An Improved Strategy for Generating Forces in Steered Molecular Dynamics: The Mechanical Unfolding of Titin, e2lip3 and Ubiquitin
title_fullStr An Improved Strategy for Generating Forces in Steered Molecular Dynamics: The Mechanical Unfolding of Titin, e2lip3 and Ubiquitin
title_full_unstemmed An Improved Strategy for Generating Forces in Steered Molecular Dynamics: The Mechanical Unfolding of Titin, e2lip3 and Ubiquitin
title_short An Improved Strategy for Generating Forces in Steered Molecular Dynamics: The Mechanical Unfolding of Titin, e2lip3 and Ubiquitin
title_sort improved strategy for generating forces in steered molecular dynamics: the mechanical unfolding of titin, e2lip3 and ubiquitin
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2947501/
https://www.ncbi.nlm.nih.gov/pubmed/20927369
http://dx.doi.org/10.1371/journal.pone.0013068
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