{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T13:29:25Z","timestamp":1789046965555,"version":"build-2803163510"},"reference-count":36,"publisher":"American Chemical Society (ACS)","issue":"36","license":[{"start":{"date-parts":[[2026,8,31]],"date-time":"2026-08-31T00:00:00Z","timestamp":1788134400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100021856","name":"Ministero dell'Universit? e della Ricerca","doi-asserted-by":"publisher","award":["P2022EKHKL"],"award-info":[{"award-number":["P2022EKHKL"]}],"id":[{"id":"10.13039\/501100021856","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,9,10]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Membrane fusion is essential for cellular communication and function, and understanding how two lipid bilayers merge is the key to informing therapeutic strategies. Functionalized nanoparticles have recently emerged as synthetic fusogens, but the molecular mechanisms driving this process remain unclear, partly because fusion involves transitions over high free-energy barriers, which are difficult to capture in molecular simulations. While enhanced sampling methods can address this problem, they also rely on the definition of collective variables, which are especially hard to define for fusion as it arises from the collective rearrangement of many molecules and cannot be easily reduced to a simple intuitive coordinate. Here, we study stalk formation, the first step of fusion, mediated by an amphiphilic gold nanoparticle, by employing an enhanced sampling strategy based on the committor function, machine-learned through a self-consistent procedure. This method requires minimal prior knowledge of the system and leverages the learned committor function as an effective collective variable, enabling the uniform sampling of the entire pathway. From the resulting reactive trajectories and extensive transition region sampling, we obtained converged free-energy estimates and mechanistic insight into stalk formation.<\/jats:p>","DOI":"10.1021\/acs.jpclett.6c02454","type":"journal-article","created":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T02:11:05Z","timestamp":1788401465000},"page":"10518-10524","source":"Crossref","is-referenced-by-count":0,"title":["Let\u2019s Stalk about Membranes: Committor-Based\nEnhanced Sampling of Stalk Formation"],"prefix":"10.1021","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0009-0004-5673-7981","authenticated-orcid":true,"given":"Giorgia","family":"Rossi","sequence":"first","affiliation":[{"name":"Italian Institute of Technology , , ,","place":["Genova, Italy, 16156"]},{"name":"University of Genova , , ,","place":["Genova, Italy, 16146"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2042-0232","authenticated-orcid":true,"given":"Enrico","family":"Trizio","sequence":"additional","affiliation":[{"name":"Italian Institute of Technology , , ,","place":["Genova, Italy, 16156"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3682-9086","authenticated-orcid":true,"given":"Davide","family":"Bochicchio","sequence":"additional","affiliation":[{"name":"University of Genova , , ,","place":["Genova, Italy, 16146"]},{"name":"INFN Sezione di Genova , ,","place":["Genova, Italy, 16146"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6916-2049","authenticated-orcid":true,"given":"Giulia","family":"Rossi","sequence":"additional","affiliation":[{"name":"University of Genova , , ,","place":["Genova, Italy, 16146"]},{"name":"INFN Sezione di Genova , ,","place":["Genova, Italy, 16146"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6550-3272","authenticated-orcid":true,"given":"Michele","family":"Parrinello","sequence":"additional","affiliation":[{"name":"Italian Institute of Technology , , ,","place":["Genova, Italy, 16156"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,8,31]]},"reference":[{"key":"2026091008091947300_cit1","doi-asserted-by":"publisher","first-page":"1572","DOI":"10.1039\/C0CS00115E","article-title":"Model Systems\nfor Membrane Fusion","volume":"40","author":"Marsden","year":"2011","journal-title":"Chem. 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U.S.A."},{"key":"2026091008091947300_cit5","doi-asserted-by":"publisher","first-page":"4675","DOI":"10.1039\/D3NA00430A","article-title":"Nanoparticle-Induced\nBiomembrane\nFusion: Unraveling the Effect of Core Size on Stalk Formation","volume":"5","author":"Brosio","year":"2023","journal-title":"Nanoscale Advances"},{"key":"2026091008091947300_cit6","doi-asserted-by":"publisher","first-page":"2207125","DOI":"10.1002\/smll.202207125","article-title":"Cholesterol-Containing\nLiposomes Decorated With Au Nanoparticles as Minimal Tunable Fusion\nMachinery","volume":"19","author":"Canepa","year":"2023","journal-title":"Small"},{"key":"2026091008091947300_cit7","doi-asserted-by":"publisher","first-page":"8923","DOI":"10.1039\/D4NR04851B","article-title":"Physical Determinants\nof Nanoparticle-Mediated Lipid Membrane Fusion","volume":"17","author":"Leonardini","year":"2025","journal-title":"Nanoscale"},{"key":"2026091008091947300_cit8","doi-asserted-by":"publisher","first-page":"pgac156","DOI":"10.1093\/pnasnexus\/pgac156","article-title":"Extracellular Vesicle Fusion Visualized\nby Cryo-Electron\nMicroscopy","volume":"1","author":"Morandi","year":"2022","journal-title":"PNAS Nexus"},{"key":"2026091008091947300_cit9","doi-asserted-by":"publisher","first-page":"1583","DOI":"10.33011\/livecoms.4.1.1583","article-title":"Enhanced Sampling\nMethods for Molecular Dynamics Simulations","volume":"4","author":"He\u0301nin","year":"2022","journal-title":"Living Journal of Computational Molecular Science"},{"key":"2026091008091947300_cit10","doi-asserted-by":"publisher","first-page":"671","DOI":"10.1021\/acs.chemrev.5c00700","article-title":"Enhanced Sampling in the Age of Machine Learning: Algorithms\nand Applications","volume":"126","author":"Zhu","year":"2026","journal-title":"Chem. Rev."},{"key":"2026091008091947300_cit11","doi-asserted-by":"publisher","first-page":"634","DOI":"10.1038\/nature24469","article-title":"A Tethering Complex\nDrives the Terminal Stage of SNARE-Dependent\nMembrane Fusion","volume":"551","author":"D\u2019Agostino","year":"2017","journal-title":"Nature"},{"key":"2026091008091947300_cit12","doi-asserted-by":"publisher","first-page":"11043","DOI":"10.1073\/pnas.1323221111","article-title":"Expansion\nof the Fusion Stalk and\nIts Implication for Biological Membrane Fusion","volume":"111","author":"Risselada","year":"2014","journal-title":"Proceedings of the National Academy of Sciences U.S.A."},{"key":"2026091008091947300_cit13","doi-asserted-by":"publisher","first-page":"2352","DOI":"10.1021\/acs.jctc.7b00106","article-title":"Probing a Continuous\nPolar Defect: A Reaction Coordinate\nfor Pore Formation in Lipid Membranes","volume":"13","author":"Hub","year":"2017","journal-title":"J. Chem.\nTheory Comput."},{"key":"2026091008091947300_cit14","doi-asserted-by":"publisher","first-page":"1229","DOI":"10.1021\/acs.jctc.0c01134","article-title":"Joint Reaction\nCoordinate for Computing the Free-Energy Landscape of Pore Nucleation\nand Pore Expansion in Lipid Membranes","volume":"17","author":"Hub","year":"2021","journal-title":"J. Chem.\nTheory Comput."},{"key":"2026091008091947300_cit15","doi-asserted-by":"publisher","first-page":"109","DOI":"10.1016\/j.chemphyslip.2014.07.010","article-title":"Mechanics\nof Membrane Fusion\/Pore Formation","volume":"185","author":"Fuhrmans","year":"2015","journal-title":"Chem. Phys.\nLipids"},{"key":"2026091008091947300_cit16","doi-asserted-by":"publisher","first-page":"228103","DOI":"10.1103\/PhysRevLett.108.228103","article-title":"Transition\nPath from Two Apposed Membranes to a Stalk Obtained by a Combination\nof Particle Simulations and String Method","volume":"108","author":"Mu\u0308ller","year":"2012","journal-title":"Phys.\nRev. Lett."},{"key":"2026091008091947300_cit17","doi-asserted-by":"publisher","first-page":"2571","DOI":"10.1073\/pnas.1818200116","article-title":"Thermodynamically Reversible Paths\nof the First Fusion Intermediate Reveal an Important Role for Membrane\nAnchors of Fusion Proteins","volume":"116","author":"Smirnova","year":"2019","journal-title":"Proceedings of the\nNational Academy of Sciences U.S.A."},{"key":"2026091008091947300_cit18","doi-asserted-by":"publisher","first-page":"6594","DOI":"10.1038\/s41467-021-26924-2","article-title":"Free Energies\nof Membrane Stalk Formation\nfrom a Lipidomics Perspective","volume":"12","author":"Poojari","year":"2021","journal-title":"Nat. Commun."},{"key":"2026091008091947300_cit19","doi-asserted-by":"publisher","first-page":"391","DOI":"10.1146\/annurev.physchem.040808.090412","article-title":"Transition-path\ntheory and path-finding algorithms\nfor the study of rare events","volume":"61","author":"E","year":"2010","journal-title":"Annu. Rev. Phys.\nChem."},{"key":"2026091008091947300_cit20","doi-asserted-by":"publisher","first-page":"451","DOI":"10.1038\/s43588-024-00645-0","article-title":"Computing the Committor with the\nCommittor to Study the Transition State Ensemble","volume":"4","author":"Kang","year":"2024","journal-title":"Nature Computational Science"},{"key":"2026091008091947300_cit21","doi-asserted-by":"publisher","first-page":"582","DOI":"10.1038\/s43588-025-00799-5","article-title":"Everything\nEverywhere All at Once:\nA Probability-Based Enhanced Sampling Approach to Rare Events","volume":"5","author":"Trizio","year":"2025","journal-title":"Nature Computational Science"},{"key":"2026091008091947300_cit22","doi-asserted-by":"publisher","first-page":"9785","DOI":"10.1021\/acscatal.5c02431","article-title":"A Machine\nLearning-Driven, Probability-Based\nApproach to Enzyme Catalysis","volume":"15","author":"Das","year":"2025","journal-title":"ACS Catal."},{"key":"2026091008091947300_cit23","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2526954123","article-title":"The role of\nfluctuations in the nucleation process","volume":"123","author":"Deng","year":"2026","journal-title":"Proceedings\nof the National Academy of Sciences U.S.A."},{"key":"2026091008091947300_cit24","doi-asserted-by":"publisher","first-page":"103201","DOI":"10.1016\/j.chempr.2026.103201","article-title":"PETase Learns from LCC: Redesigning\nEnzymatic Reactivity with Probability-Based Simulations","volume":"12","author":"Berselli","year":"2026","journal-title":"Chem"},{"key":"2026091008091947300_cit25","doi-asserted-by":"publisher","first-page":"134105","DOI":"10.1063\/5.0331622","article-title":"Ceci n\u2019est\nPas Un Committor,\nyet It Samples like One: Efficient Sampling via Approximated Committor\nFunctions","volume":"164","author":"Trizio","year":"2026","journal-title":"J. Chem. Phys."},{"key":"2026091008091947300_cit26","doi-asserted-by":"publisher","first-page":"2731","DOI":"10.1021\/acs.jpclett.0c00497","article-title":"Rethinking metadynamics: from bias potentials to probability\ndistributions","volume":"11","author":"Invernizzi","year":"2020","journal-title":"J. Phys. Chem. Lett."},{"key":"2026091008091947300_cit27","doi-asserted-by":"publisher","first-page":"3988","DOI":"10.1021\/acs.jctc.2c00152","article-title":"Exploration\nvs Convergence Speed in Adaptive-Bias Enhanced\nSampling","volume":"18","author":"Invernizzi","year":"2022","journal-title":"J. Chem. Theory Comput."},{"key":"2026091008091947300_cit28","doi-asserted-by":"publisher","first-page":"arXiv:2410.18019","DOI":"10.48550\/arXiv.2410.18019","article-title":"Advanced simulations with PLUMED:\nOPES and Machine\nLearning Collective Variables","author":"Trizio","year":"2024","journal-title":"arXiv.org, e-Print\nArch., Phys."},{"key":"2026091008091947300_cit29","doi-asserted-by":"publisher","first-page":"7812","DOI":"10.1021\/jp071097f","article-title":"The MARTINI\nForce Field: Coarse Grained Model for Biomolecular Simulations","volume":"111","author":"Marrink","year":"2007","journal-title":"J. Phys. Chem. B"},{"key":"2026091008091947300_cit30","doi-asserted-by":"publisher","first-page":"3175","DOI":"10.1021\/acs.jpclett.5b01469","article-title":"Monolayer-Protected\nAnionic Au Nanoparticles Walk into Lipid Membranes Step-by-Step","volume":"6","author":"Simonelli","year":"2015","journal-title":"J. Phys. Chem. Lett."},{"key":"2026091008091947300_cit31","doi-asserted-by":"publisher","first-page":"3261","DOI":"10.1021\/acs.jctc.6b00369","article-title":"Simulations of Pore Formation in\nLipid Membranes: Reaction\nCoordinates, Convergence, Hysteresis, and Finite-Size Effects","volume":"12","author":"Awasthi","year":"2016","journal-title":"J. Chem. Theory Comput."},{"key":"2026091008091947300_cit32","doi-asserted-by":"publisher","first-page":"4183","DOI":"10.21105\/joss.04183","article-title":"Fast k-medoids Clustering in Rust\nand Python","volume":"7","author":"Schubert","year":"2022","journal-title":"Journal of Open Source Software"},{"key":"2026091008091947300_cit33","doi-asserted-by":"publisher","first-page":"014801","DOI":"10.1063\/5.0156343","article-title":"A unified\nframework for machine learning collective variables for enhanced sampling\nsimulations: mlcolvar","volume":"159","author":"Bonati","year":"2023","journal-title":"J. Chem. Phys."},{"key":"2026091008091947300_cit34","doi-asserted-by":"publisher","first-page":"19","DOI":"10.1016\/j.softx.2015.06.001","article-title":"GROMACS: High\nPerformance\nMolecular Simulations through Multi-Level Parallelism from Laptops\nto Supercomputers","volume":"1\u20132","author":"Abraham","year":"2015","journal-title":"SoftwareX"},{"key":"2026091008091947300_cit35","doi-asserted-by":"publisher","first-page":"670","DOI":"10.1038\/s41592-019-0506-8","article-title":"Promoting\ntransparency and reproducibility in enhanced molecular simulations","volume":"16","author":"The PLUMED consortium.","year":"2019","journal-title":"Nat. Methods"},{"key":"2026091008091947300_cit36","doi-asserted-by":"publisher","first-page":"604","DOI":"10.1016\/j.cpc.2013.09.018","article-title":"PLUMED 2: New feathers for an old\nbird","volume":"185","author":"Tribello","year":"2014","journal-title":"Computer\nPhysics Communications"}],"container-title":["The Journal of Physical Chemistry Letters"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pubs.acs.org\/doi\/pdf\/10.1021\/acs.jpclett.6c02454","content-type":"application\/pdf","content-version":"vor","intended-application":"unspecified"},{"URL":"https:\/\/pubs.acs.org\/jpclcd\/article-pdf\/17\/36\/10518\/67981551\/acs.jpclett.6c02454.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/pubs.acs.org\/jpclcd\/article-pdf\/17\/36\/10518\/67981551\/acs.jpclett.6c02454.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T12:49:50Z","timestamp":1789044590000},"score":1,"resource":{"primary":{"URL":"https:\/\/pubs.acs.org\/jpclcd\/article\/17\/36\/10518\/5383263\/Let-s-Stalk-about-Membranes-Committor-Based"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,31]]},"references-count":36,"journal-issue":{"issue":"36","published-online":{"date-parts":[[2026,8,31]]},"published-print":{"date-parts":[[2026,9,10]]}},"URL":"https:\/\/doi.org\/10.1021\/acs.jpclett.6c02454","relation":{},"ISSN":["1948-7185"],"issn-type":[{"value":"1948-7185","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,31]]}}}