{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,19]],"date-time":"2026-08-19T17:53:59Z","timestamp":1787162039638,"version":"build-2736575974"},"reference-count":58,"publisher":"AIP Publishing","issue":"14","funder":[{"name":"Eu European Regional Development Fund","award":["TEAM\/2011-7\/6"],"award-info":[{"award-number":["TEAM\/2011-7\/6"]}]},{"DOI":"10.13039\/100007224","name":"NAFOSTED","doi-asserted-by":"crossref","award":["106-YS.02-2013.01"],"award-info":[{"award-number":["106-YS.02-2013.01"]}],"id":[{"id":"10.13039\/100007224","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Polish Ministry of Science and Higher Education","award":["IP2012 016872"],"award-info":[{"award-number":["IP2012 016872"]}]},{"name":"Polish NCN Foundation","award":["2011\/01\/B\/NZ1\/01622"],"award-info":[{"award-number":["2011\/01\/B\/NZ1\/01622"]}]}],"content-domain":{"domain":["pubs.aip.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2015,4,14]]},"abstract":"<jats:p>Fibril formation resulting from protein misfolding and aggregation is a hallmark of several neurodegenerative diseases such as Alzheimer\u2019s and Parkinson\u2019s diseases. Despite the fact that the fibril formation process is very slow and thus poses a significant challenge for theoretical and experimental studies, a number of alternative pictures of molecular mechanisms of amyloid fibril formation have been recently proposed. What seems to be common for the majority of the proposed models is that fibril elongation involves the formation of pre-nucleus seeds prior to the creation of a critical nucleus. Once the size of the pre-nucleus seed reaches the critical nucleus size, its thermal fluctuations are expected to be small and the resulting nucleus provides a template for sequential (one-by-one) accommodation of added monomers. The effect of template fluctuations on fibril formation rates has not been explored either experimentally or theoretically so far. In this paper, we make the first attempt at solving this problem by two sets of simulations. To mimic small template fluctuations, in one set, monomers of the preformed template are kept fixed, while in the other set they are allowed to fluctuate. The kinetics of addition of a new peptide onto the template is explored using all-atom simulations with explicit water and the GROMOS96 43a1 force field and simple lattice models. Our result demonstrates that preformed template fluctuations can modulate protein aggregation rates and pathways. The association of a nascent monomer with the template obeys the kinetics partitioning mechanism where the intermediate state occurs in a fraction of routes to the protofibril. It was shown that template immobility greatly increases the time of incorporating a new peptide into the preformed template compared to the fluctuating template case. This observation has also been confirmed by simulation using lattice models and may be invoked to understand the role of template fluctuations in slowing down fibril elongation in vivo.<\/jats:p>","DOI":"10.1063\/1.4917073","type":"journal-article","created":{"date-parts":[[2015,4,13]],"date-time":"2015-04-13T13:09:24Z","timestamp":1428930564000},"update-policy":"https:\/\/doi.org\/10.1063\/aip-crossmark-policy-page","source":"Crossref","is-referenced-by-count":17,"title":["Preformed template fluctuations promote fibril formation: Insights from lattice and all-atom models"],"prefix":"10.1063","volume":"142","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1704-9797","authenticated-orcid":false,"given":"Maksim","family":"Kouza","sequence":"first","affiliation":[{"name":"University of Warsaw 1 Faculty of Chemistry, , ul. Pasteura 1, 02-093 Warszaw, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5642-3641","authenticated-orcid":false,"given":"Nguyen Truong","family":"Co","sequence":"additional","affiliation":[{"name":"Institute of Technology, National University of HCM City 2 Department of Physics, , 268 Ly Thuong Kiet Street, District 10, Ho Chi Minh City, Viet Nam"},{"name":"Institute for Computational Science and Technology 3 , Quang Trung Software City, Tan Chanh Hiep Ward, District 12, Ho Chi Minh City, Vietnam"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Phuong H.","family":"Nguyen","sequence":"additional","affiliation":[{"name":"IBPC, Universite Paris 7 4 Laboratoire de Biochimie Theorique, UPR 9080 CNRS, , 13 rue Pierre et Marie Curie, 75005 Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrzej","family":"Kolinski","sequence":"additional","affiliation":[{"name":"University of Warsaw 1 Faculty of Chemistry, , ul. Pasteura 1, 02-093 Warszaw, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mai Suan","family":"Li","sequence":"additional","affiliation":[{"name":"Polish Academy of Sciences 5 Institute of Physics, , Al. Lotnikow 32\/46, 02-668 Warsaw, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"317","published-online":{"date-parts":[[2015,4,13]]},"reference":[{"key":"2023073109452078500_c1","doi-asserted-by":"publisher","first-page":"333","DOI":"10.1146\/annurev.biochem.75.101304.123901","article-title":"Protein misfolding, functional amyloid, and human disease","volume":"75","year":"2006","journal-title":"Annu. Rev. Biochem."},{"key":"2023073109452078500_c2","doi-asserted-by":"publisher","first-page":"1125","DOI":"10.1073\/pnas.93.3.1125","article-title":"On the nucleation and growth of \u03b2-protein fibrils: Detection of nuclei and quantitation of rate constants","volume":"93","year":"1996","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"2023073109452078500_c3","doi-asserted-by":"publisher","first-page":"60","DOI":"10.1016\/S0959-440X(99)00049-4","article-title":"Amyloid fibrillogenesis: Themes and variations","volume":"10","year":"2000","journal-title":"Curr. Opin. Struct. Biol."},{"key":"2023073109452078500_c4","doi-asserted-by":"publisher","first-page":"1031","DOI":"10.1016\/S0969-2126(02)00809-2","article-title":"Ideas of order for amyloid fibril structure","volume":"10","year":"2002","journal-title":"Structure"},{"key":"2023073109452078500_c5","doi-asserted-by":"publisher","first-page":"900","DOI":"10.1038\/nature02264","article-title":"Folding proteins in fatal ways","volume":"426","year":"2003","journal-title":"Nature"},{"key":"2023073109452078500_c6","doi-asserted-by":"publisher","first-page":"1259","DOI":"10.1126\/science.1093078","article-title":"Protein chemistry. In the footsteps of alchemists","volume":"304","year":"2004","journal-title":"Science"},{"key":"2023073109452078500_c7","doi-asserted-by":"publisher","first-page":"S10","DOI":"10.1038\/nm1066","article-title":"Protein aggregation and neurodegenerative disease","volume":"10","year":"2004","journal-title":"Nat. Med."},{"key":"2023073109452078500_c8","doi-asserted-by":"publisher","first-page":"S2","DOI":"10.1038\/nm1067","article-title":"Molecular pathways to neurodegeneration","volume":"10","year":"2004","journal-title":"Nat. Med."},{"key":"2023073109452078500_c9","doi-asserted-by":"publisher","first-page":"16388","DOI":"10.1021\/ja0561901","article-title":"Tertiary contact formation in alpha-synuclein probed by electron transfer","volume":"127","year":"2005","journal-title":"J. Am. Chem. Soc."},{"key":"2023073109452078500_c10","doi-asserted-by":"publisher","first-page":"235","DOI":"10.1016\/S0065-3233(06)73008-X","article-title":"Structural models of amyloid-like fibrils","volume":"73","year":"2006","journal-title":"Adv. Protein Chem."},{"key":"2023073109452078500_c11","doi-asserted-by":"publisher","first-page":"625","DOI":"10.1016\/j.febslet.2013.02.010","article-title":"Amino acid sequence determinants in self-assembly of insulin chiral amyloid superstructures: Role of C-terminus of B-chain in association of fibrils","volume":"587","year":"2013","journal-title":"FEBS Lett."},{"key":"2023073109452078500_c12","doi-asserted-by":"publisher","first-page":"2642","DOI":"10.1002\/pro.5560071218","article-title":"Effect of denaturant and protein concentrations upon protein refolding and aggregation: A simple lattice model","volume":"7","year":"1998","journal-title":"Protein Sci."},{"key":"2023073109452078500_c13","doi-asserted-by":"publisher","first-page":"14126","DOI":"10.1073\/pnas.212206899","article-title":"Stabilities and conformations of Alzheimer\u2019s \u03b2-amyloid peptide oligomers (a\u03b2 (16-22 \u2019) a\u03b2 (16-35 \u2019) and a\u03b2 (10-35)): Sequence effects","volume":"99","year":"2002","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"2023073109452078500_c14","doi-asserted-by":"publisher","first-page":"217","DOI":"10.1002\/1097-0134(20010201)42:2%3C217::AID-PROT90%3E3.0.CO;2-N","article-title":"Energy landscape theory for Alzheimer\u2019s \u03b2-peptide fibril elongation","volume":"42","year":"2001","journal-title":"Proteins: Struct., Funct., Bioinf."},{"key":"2023073109452078500_c15","doi-asserted-by":"publisher","first-page":"187","DOI":"10.1006\/jmbi.2001.4845","article-title":"Protein refolding versus aggregation: Computer simulations on an intermediate-resolution protein model","volume":"312","year":"2001","journal-title":"J. Mol. Biol."},{"key":"2023073109452078500_c16","doi-asserted-by":"publisher","first-page":"5154","DOI":"10.1073\/pnas.0835307100","article-title":"The role of side-chain interactions in the early steps of aggregation: Molecular dynamics simulations of an amyloid-forming peptide from the yeast prion Sup351","volume":"100","year":"2003","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"2023073109452078500_c17","doi-asserted-by":"publisher","first-page":"295","DOI":"10.1016\/S0969-2126(03)00031-5","article-title":"Dissecting the assembly of A\u03b2 (16-22) amyloid peptides into antiparallel \u03b2 sheets","volume":"11","year":"2003","journal-title":"Structure"},{"key":"2023073109452078500_c18","doi-asserted-by":"publisher","first-page":"3657","DOI":"10.1529\/biophysj.104.046839","article-title":"Oligomerization of amyloid A\u03b2(16-22) peptides using hydrogen bonds and hydrophobicity forces","volume":"87","year":"2004","journal-title":"Biophys. J."},{"key":"2023073109452078500_c19","doi-asserted-by":"publisher","first-page":"3648","DOI":"10.1529\/biophysj.104.047688","article-title":"Sampling the self-assembly pathways of KFFE hexamers","volume":"87","year":"2004","journal-title":"Biophys. J."},{"key":"2023073109452078500_c20","doi-asserted-by":"publisher","first-page":"804","DOI":"10.1016\/j.jmb.2005.08.066","article-title":"Molecular dynamics simulations of Alzheimer\u2019s \u03b2-amyloid protofilaments","volume":"353","year":"2005","journal-title":"J. Mol. Biol."},{"key":"2023073109452078500_c21","doi-asserted-by":"publisher","first-page":"7835","DOI":"10.1073\/pnas.0409389102","article-title":"Theoretical model of prions: A misfolded protein induces misfolding","volume":"102","year":"2005","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"2023073109452078500_c22","doi-asserted-by":"publisher","first-page":"65","DOI":"10.1186\/1471-2105-8-65","article-title":"Aggrescan: A server for the prediction and evaluation of hot spots of aggregation in polypeptides","volume":"8","year":"2007","journal-title":"BMC Bioinf."},{"key":"2023073109452078500_c23","doi-asserted-by":"publisher","first-page":"1202","DOI":"10.1016\/j.jmb.2007.02.066","article-title":"Dissociation of a \u03b2 (16-22) amyloid fibrils probed by molecular dynamics","volume":"368","year":"2007","journal-title":"J. Mol. Biol."},{"key":"2023073109452078500_c24","doi-asserted-by":"publisher","first-page":"245104","DOI":"10.1063\/1.2739547","article-title":"Self-assembly of \u03b2-sheet forming peptides into chiral fibrillar aggregates","volume":"126","year":"2007","journal-title":"J. Chem. Phys."},{"key":"2023073109452078500_c25","doi-asserted-by":"publisher","first-page":"275","DOI":"10.1016\/j.jmb.2006.11.015","article-title":"The structure of the Alzheimer amyloid \u03b2 10-35 peptide probed through replica-exchange molecular dynamics simulations in explicit solvent","volume":"366","year":"2007","journal-title":"J. Mol. Biol."},{"key":"2023073109452078500_c26","doi-asserted-by":"publisher","first-page":"218101","DOI":"10.1103\/PhysRevLett.105.218101","article-title":"Determination of factors governing fibrillogenesis of polypeptide chains using lattice models","volume":"105","year":"2010","journal-title":"Phys. Rev. Lett."},{"key":"2023073109452078500_c27","doi-asserted-by":"publisher","first-page":"12978","DOI":"10.1021\/jp2050993","article-title":"A study of the -helical intermediate preceding the aggregation of the amino-terminal fragment of the amyloid peptide (A(1-28))","volume":"115","year":"2011","journal-title":"J. Phys. Chem. B"},{"key":"2023073109452078500_c28","doi-asserted-by":"publisher","first-page":"6288","DOI":"10.1021\/bi992933h","article-title":"Alzheimer\u2019s disease amyloid propagation by a template-dependent dock-lock mechanism","volume":"39","year":"2000","journal-title":"Biochemistry"},{"key":"2023073109452078500_c29","doi-asserted-by":"publisher","first-page":"67","DOI":"10.1016\/j.ab.2004.01.014","article-title":"Kinetic analysis of \u03b2-amyloid fibril elongation","volume":"328","year":"2004","journal-title":"Anal. Biochem."},{"key":"2023073109452078500_c30","doi-asserted-by":"publisher","first-page":"111","DOI":"10.1073\/pnas.0607440104","article-title":"Monomer adds to preformed structured oligomers of A\u03b2-peptides by a two-stage dock-lock mechanism","volume":"104","year":"2007","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"2023073109452078500_c31","doi-asserted-by":"publisher","first-page":"11948","DOI":"10.1073\/pnas.0902473106","article-title":"Dynamics of locking of peptides onto growing amyloid fibrils","volume":"106","year":"2009","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"2023073109452078500_c32","doi-asserted-by":"publisher","first-page":"1055","DOI":"10.1016\/0092-8674(93)90635-4","article-title":"Seeding one-dimensional crystallization of amyloid: A pathogenic mechanism in Alzheimer\u2019s disease and scrapie?","volume":"73","year":"1993","journal-title":"Cell"},{"key":"2023073109452078500_c33","doi-asserted-by":"publisher","first-page":"1317","DOI":"10.1126\/science.289.5483.1317","article-title":"Nucleated conformational conversion and the replication of conformational information by a prion determinant","volume":"289","year":"2000","journal-title":"Science"},{"key":"2023073109452078500_c34","doi-asserted-by":"publisher","first-page":"1582","DOI":"10.1371\/journal.pbio.0020321","article-title":"Mechanism of prion propagation: Amyloid growth occurs by monomer addition","volume":"2","year":"2004","journal-title":"PLoS Biol."},{"key":"2023073109452078500_c35","doi-asserted-by":"publisher","first-page":"537","DOI":"10.1016\/j.jmb.2010.09.057","article-title":"Mechanism of fiber assembly: Treatment of a peptide aggregation with a coarse-grained united-residue force field","volume":"404","year":"2010","journal-title":"J. Mol. Biol."},{"key":"2023073109452078500_c36","volume-title":"Biomolecular Simulation: The GROMOS96 Manual and User Guide","year":"1996"},{"key":"2023073109452078500_c37","doi-asserted-by":"publisher","first-page":"175101","DOI":"10.1063\/1.2989981","article-title":"Probing the mechanisms of fibril formation using lattice models","volume":"129","year":"2008","journal-title":"J. Chem. Phys."},{"key":"2023073109452078500_c38","volume-title":"Intermolecular Forces","year":"1996"},{"key":"2023073109452078500_c39","doi-asserted-by":"publisher","first-page":"9893","DOI":"10.3390\/ijms14059893","article-title":"Combining coarse-grained protein models with replica-exchange all-atom molecular dynamics","volume":"14","year":"2013","journal-title":"Int. J. Mol. Sci."},{"key":"2023073109452078500_c40","doi-asserted-by":"publisher","first-page":"215103","DOI":"10.1063\/1.3272275","article-title":"Protein mechanical unfolding: Importance of non-native conformations","volume":"131","year":"2009","journal-title":"J. Chem. Phys."},{"key":"2023073109452078500_c41","doi-asserted-by":"publisher","first-page":"165104","DOI":"10.1063\/1.3415372","article-title":"Relationship between population of the fibril-prone conformation in the monomeric state and oligomer formation times of peptides: Insights from all-atom simulations","volume":"132","year":"2010","journal-title":"J. Chem. Phys."},{"key":"2023073109452078500_c42","doi-asserted-by":"publisher","first-page":"9778","DOI":"10.1039\/c1cp20323a","article-title":"Effects of all-atom force fields on amyloid oligomerization: Replica exchange molecular dynamics simulations of the A\u03b2 (16-22) dimer and trimer","volume":"13","year":"2011","journal-title":"Phys. Chem. Chem. Phys."},{"key":"2023073109452078500_c43","doi-asserted-by":"publisher","first-page":"5191","DOI":"10.1021\/bi00015a033","article-title":"1H NMR of A\u03b2 amyloid peptide congeners in water solution. Conformational changes correlate with plaque competence","volume":"34","year":"1995","journal-title":"Biochemistry"},{"key":"2023073109452078500_c44","doi-asserted-by":"publisher","first-page":"45","DOI":"10.1002\/prot.20310","article-title":"Energy landscape of a small peptide revealed by dihedral angle principle component analysis","volume":"58","year":"2005","journal-title":"Proteins: Struct., Funct., Bioinf."},{"key":"2023073109452078500_c45","doi-asserted-by":"publisher","first-page":"10748","DOI":"10.1063\/1.1809588","article-title":"Replica exchange molecular dynamics simulations of amyloid peptide aggregation","volume":"121","year":"2004","journal-title":"J. Chem. Phys."},{"key":"2023073109452078500_c46","doi-asserted-by":"crossref","first-page":"349","DOI":"10.18388\/abp.2004_3575","article-title":"Protein modeling and structure prediction with a reduced representation","volume":"51","year":"2004","journal-title":"Acta Biochimica Polonica"},{"key":"2023073109452078500_c47","doi-asserted-by":"publisher","first-page":"7026","DOI":"10.1021\/jp301720w","article-title":"From coarse-grained to atomic-level characterization of protein dynamics: Transition state for the folding of b domain of protein a","volume":"116","year":"2012","journal-title":"J. Phys. Chem. B"},{"issue":"1","key":"2023073109452078500_c48","doi-asserted-by":"publisher","first-page":"119","DOI":"10.1021\/ct300854w","article-title":"Consistent view of protein fluctuations from all-atom molecular dynamics and coarse-grained dynamics with knowledge-based force-field","volume":"9","year":"2013","journal-title":"J. Chem. Theory Comput."},{"key":"2023073109452078500_c49","doi-asserted-by":"publisher","first-page":"5153","DOI":"10.1063\/1.431297","article-title":"Analysis of monte-carlo results on kinetics of lattice polymer-chains with excluded volume","volume":"63","year":"1975","journal-title":"J. Chem. Phys."},{"key":"2023073109452078500_c50","doi-asserted-by":"publisher","first-page":"8302","DOI":"10.1021\/jp025837q","article-title":"Dependence of folding rates on protein length","volume":"106","year":"2002","journal-title":"J. Phys. Chem. B"},{"key":"2023073109452078500_c51","doi-asserted-by":"publisher","first-page":"095101","DOI":"10.1063\/1.4749257","article-title":"New method for determining size of critical nucleus of fibril formation of polypeptide chains","volume":"137","year":"2012","journal-title":"J. Chem. Phys."},{"key":"2023073109452078500_c52","doi-asserted-by":"publisher","first-page":"185101","DOI":"10.1063\/1.4804299","article-title":"Dual effect of crowders on fibrillation kinetics of polypeptide chains revealed by lattice models","volume":"138","year":"2013","journal-title":"J. Chem. Phys."},{"key":"2023073109452078500_c53","doi-asserted-by":"publisher","first-page":"16938","DOI":"10.1073\/pnas.1112600108","article-title":"Molecular basis for amyloid-\u03b2 polymorphism","volume":"108","year":"2011","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"2023073109452078500_c54","doi-asserted-by":"publisher","first-page":"1684","DOI":"10.1103\/PhysRevLett.83.1684","article-title":"Scaling of folding properties in simple models of proteins","volume":"83","year":"1999","journal-title":"Phys. Rev. Lett."},{"key":"2023073109452078500_c55","doi-asserted-by":"publisher","first-page":"970","DOI":"10.1103\/PhysRevE.59.970","article-title":"Folding in two-dimensional off-lattice models of proteins","volume":"59","year":"1999","journal-title":"Phys. Rev. E"},{"key":"2023073109452078500_c56","doi-asserted-by":"publisher","first-page":"14","DOI":"10.1007\/s002140050198","article-title":"Kinetic partitioning mechanism as a unifying theme in the folding of biomolecules","volume":"96","year":"1997","journal-title":"Theor. Chem. Acc."},{"key":"2023073109452078500_c57","doi-asserted-by":"publisher","first-page":"2269","DOI":"10.1002\/anie.200250684","article-title":"A conformational flexibility scale for amino acids in peptides","volume":"42","year":"2003","journal-title":"Angew. Chem., Int. Ed."},{"key":"2023073109452078500_c58","unstructured":"See supplementary material at http:\/\/dx.doi.org\/10.1063\/1.4917073  for the structure and fibril formation times of the double layer system, and figures on time dependence of order parameterP2 and HBs of double layer (8 + 1) and single layer (4 + 1) systems."}],"container-title":["The Journal of Chemical Physics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pubs.aip.org\/aip\/jcp\/article-pdf\/doi\/10.1063\/1.4917073\/13527155\/145104_1_online.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/pubs.aip.org\/aip\/jcp\/article-pdf\/doi\/10.1063\/1.4917073\/13527155\/145104_1_online.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,7,31]],"date-time":"2023-07-31T05:45:41Z","timestamp":1690782341000},"score":1,"resource":{"primary":{"URL":"https:\/\/pubs.aip.org\/jcp\/article\/142\/14\/145104\/900211\/Preformed-template-fluctuations-promote-fibril"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2015,4,13]]},"references-count":58,"journal-issue":{"issue":"14","published-print":{"date-parts":[[2015,4,14]]}},"URL":"https:\/\/doi.org\/10.1063\/1.4917073","relation":{},"ISSN":["0021-9606","1089-7690"],"issn-type":[{"value":"0021-9606","type":"print"},{"value":"1089-7690","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2015,4,14]]},"published":{"date-parts":[[2015,4,13]]},"article-number":"145104"}}