{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,9]],"date-time":"2026-07-09T02:01:15Z","timestamp":1783562475333,"version":"3.55.0"},"update-to":[{"DOI":"10.1371\/journal.pcbi.1009625","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2021,12,17]],"date-time":"2021-12-17T00:00:00Z","timestamp":1639699200000}}],"reference-count":42,"publisher":"Public Library of Science (PLoS)","issue":"11","license":[{"start":{"date-parts":[[2021,11,29]],"date-time":"2021-11-29T00:00:00Z","timestamp":1638144000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["Sonderforschungsbereich 1035, Projektnummer 201302640, project B02"],"award-info":[{"award-number":["Sonderforschungsbereich 1035, Projektnummer 201302640, project B02"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Leibniz Supercomputing Center","award":["grant pr27za"],"award-info":[{"award-number":["grant pr27za"]}]}],"content-domain":{"domain":["www.ploscompbiol.org"],"crossmark-restriction":false},"short-container-title":["PLoS Comput Biol"],"abstract":"<jats:p>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 <jats:italic>Thermus Thermophilus<\/jats:italic> 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\u2019-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.<\/jats:p>","DOI":"10.1371\/journal.pcbi.1009625","type":"journal-article","created":{"date-parts":[[2021,11,29]],"date-time":"2021-11-29T18:55:32Z","timestamp":1638212132000},"page":"e1009625","update-policy":"https:\/\/doi.org\/10.1371\/journal.pcbi.corrections_policy","source":"Crossref","is-referenced-by-count":9,"title":["Binding-induced functional-domain motions in the Argonaute characterized by adaptive advanced sampling"],"prefix":"10.1371","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1973-0401","authenticated-orcid":true,"given":"Danial","family":"Pourjafar-Dehkordi","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5163-2663","authenticated-orcid":true,"given":"Martin","family":"Zacharias","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2021,11,29]]},"reference":[{"key":"pcbi.1009625.ref001","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1146\/annurev-biophys-083012-130404","article-title":"Molecular Mechanisms of RNA Interference.","volume":"42","author":"RC Wilson","year":"2013","journal-title":"Annu Rev Biophys"},{"key":"pcbi.1009625.ref002","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1146\/annurev.cellbio.23.090506.123406","article-title":"microRNA Functions.","volume":"23","author":"N Bushati","year":"2007","journal-title":"Annu Rev Cell Dev Biol"},{"key":"pcbi.1009625.ref003","doi-asserted-by":"crossref","first-page":"2619","DOI":"10.1016\/j.jmb.2017.07.018","article-title":"Structural Foundations of RNA Silencing by Argonaute","volume":"429","author":"J Sheu-Gruttadauria","year":"2017","journal-title":"J Mol Biol"},{"key":"pcbi.1009625.ref004","doi-asserted-by":"crossref","first-page":"743","DOI":"10.1038\/nsmb.2879","article-title":"The evolutionary journey of Argonaute proteins","volume":"21","author":"DC Swarts","year":"2014","journal-title":"Nat Struct Mol Biol"},{"key":"pcbi.1009625.ref005","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1016\/B978-0-12-404741-9.00004-0","article-title":"Structure and Mechanism of Argonaute Proteins.","author":"NT Schirle","year":"2012","journal-title":"The Enzymes. 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