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Binding-induced functional-domain motions in the Argonaute characterized by adaptive advanced sampling

Argonaute proteins in combination with short microRNA (miRNAs) can target mRNA molecules for translation inhibition or degradation and play a key role in many regulatory processes. The miRNAs act as guide RNAs that associate with Argonaute and the complementary mRNA target region. The complex format...

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Autores principales: Pourjafar-Dehkordi, Danial, Zacharias, Martin
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8683029/
https://www.ncbi.nlm.nih.gov/pubmed/34843451
http://dx.doi.org/10.1371/journal.pcbi.1009625
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author Pourjafar-Dehkordi, Danial
Zacharias, Martin
author_facet Pourjafar-Dehkordi, Danial
Zacharias, Martin
author_sort Pourjafar-Dehkordi, Danial
collection PubMed
description Argonaute proteins in combination with short microRNA (miRNAs) can target mRNA molecules for translation inhibition or degradation and play a key role in many regulatory processes. The miRNAs act as guide RNAs that associate with Argonaute and the complementary mRNA target region. The complex formation results in activation of Argonaute and specific cleavage of the target mRNA. Both the binding and activation processes involve essential domain rearrangements of functional importance. For the Thermus Thermophilus Argonaute (TtAgo) system guide-bound (binary) and guide/target-bound (ternary) complexes are known but how the binding of guide and target mediate domain movements is still not understood. We have studied the Argonaute domain motion in apo and guide/target bound states using Molecular Dynamics simulations and a Hamiltonian replica exchange (H-REMD) method that employs a specific biasing potential to accelerate domain motions. The H-REMD technique indicates sampling of a much broader distribution of domain arrangements both in the apo as well as binary and ternary complexes compared to regular MD simulations. In the apo state domain arrangements corresponding to more compact (closed) states are mainly sampled which undergo an opening upon guide and guide/target binding. Whereas only limited overlap in domain geometry between apo and bound states was found, a larger similarity in the domain distribution is observed for the simulations of binary and ternary complexes. Comparative simulations on ternary complexes with 15 or 16 base pairs (bp) formed between guide and target strands (instead of 14) resulted in dissociation of the 3’-guide strand from the PAZ domain and domain rearrangement. This agrees with the experimental observation that guide-target pairing beyond 14 bps is required for activation and gives a mechanistic explanation for the experimentally observed activation process.
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spelling pubmed-86830292021-12-18 Binding-induced functional-domain motions in the Argonaute characterized by adaptive advanced sampling Pourjafar-Dehkordi, Danial Zacharias, Martin PLoS Comput Biol Research Article Argonaute proteins in combination with short microRNA (miRNAs) can target mRNA molecules for translation inhibition or degradation and play a key role in many regulatory processes. The miRNAs act as guide RNAs that associate with Argonaute and the complementary mRNA target region. The complex formation results in activation of Argonaute and specific cleavage of the target mRNA. Both the binding and activation processes involve essential domain rearrangements of functional importance. For the Thermus Thermophilus Argonaute (TtAgo) system guide-bound (binary) and guide/target-bound (ternary) complexes are known but how the binding of guide and target mediate domain movements is still not understood. We have studied the Argonaute domain motion in apo and guide/target bound states using Molecular Dynamics simulations and a Hamiltonian replica exchange (H-REMD) method that employs a specific biasing potential to accelerate domain motions. The H-REMD technique indicates sampling of a much broader distribution of domain arrangements both in the apo as well as binary and ternary complexes compared to regular MD simulations. In the apo state domain arrangements corresponding to more compact (closed) states are mainly sampled which undergo an opening upon guide and guide/target binding. Whereas only limited overlap in domain geometry between apo and bound states was found, a larger similarity in the domain distribution is observed for the simulations of binary and ternary complexes. Comparative simulations on ternary complexes with 15 or 16 base pairs (bp) formed between guide and target strands (instead of 14) resulted in dissociation of the 3’-guide strand from the PAZ domain and domain rearrangement. This agrees with the experimental observation that guide-target pairing beyond 14 bps is required for activation and gives a mechanistic explanation for the experimentally observed activation process. Public Library of Science 2021-11-29 /pmc/articles/PMC8683029/ /pubmed/34843451 http://dx.doi.org/10.1371/journal.pcbi.1009625 Text en © 2021 Pourjafar-Dehkordi, Zacharias https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Pourjafar-Dehkordi, Danial
Zacharias, Martin
Binding-induced functional-domain motions in the Argonaute characterized by adaptive advanced sampling
title Binding-induced functional-domain motions in the Argonaute characterized by adaptive advanced sampling
title_full Binding-induced functional-domain motions in the Argonaute characterized by adaptive advanced sampling
title_fullStr Binding-induced functional-domain motions in the Argonaute characterized by adaptive advanced sampling
title_full_unstemmed Binding-induced functional-domain motions in the Argonaute characterized by adaptive advanced sampling
title_short Binding-induced functional-domain motions in the Argonaute characterized by adaptive advanced sampling
title_sort binding-induced functional-domain motions in the argonaute characterized by adaptive advanced sampling
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8683029/
https://www.ncbi.nlm.nih.gov/pubmed/34843451
http://dx.doi.org/10.1371/journal.pcbi.1009625
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