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Peptides are a prominent class of such molecules, which include natural and man-developed antimicrobial and cell-penetrating peptides. However, the necessary peptide properties for translocation remain elusive. Computer simulations could uncover these properties once we have a good collective variable (CV) that accurately describes the translocation process. Here, we developed a new CV, which includes a description of peptide insertion, local membrane deformation, and peptide internal degrees of freedom related to its charged groups. By comparison of CVs, we demonstrated that all these components are necessary for an accurate description of peptide translocation. Moreover, the advantages and disadvantages of three common methods for free-energy calculations with our CV were evaluated using the MARTINI coarse-grained model: umbrella sampling, umbrella sampling with replica exchange, and metadynamics. The developed CV leads to the reliable and effective calculation of the free energy of peptide translocation, and thus, it could be useful in the design of spontaneously translocating peptides.<\/jats:p>","DOI":"10.1021\/acs.jcim.0c01312","type":"journal-article","created":{"date-parts":[[2021,2,10]],"date-time":"2021-02-10T16:25:48Z","timestamp":1612974348000},"page":"819-830","source":"Crossref","is-referenced-by-count":47,"title":["Selecting Collective Variables and Free-Energy Methods\nfor Peptide Translocation across Membranes"],"prefix":"10.1021","volume":"61","author":[{"given":"Ivo","family":"Kabelka","sequence":"first","affiliation":[{"name":"Masaryk University , , Kamenice 753\/5 , ,","place":["Brno, Czech Republic, 625 00"]},{"name":"Masaryk University , , Kamenice 5 , ,","place":["Brno, Czech Republic, 625 00"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Radim","family":"Broz\u030cek","sequence":"additional","affiliation":[{"name":"Masaryk University , , Kamenice 753\/5 , ,","place":["Brno, Czech Republic, 625 00"]},{"name":"Masaryk University , , Kamenice 5 , ,","place":["Brno, Czech Republic, 625 00"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7610-658X","authenticated-orcid":true,"given":"Robert","family":"Va\u0301cha","sequence":"additional","affiliation":[{"name":"Masaryk University , , Kamenice 753\/5 , ,","place":["Brno, Czech Republic, 625 00"]},{"name":"Masaryk University , , Kamenice 5 , ,","place":["Brno, Czech Republic, 625 00"]},{"name":"Masaryk University , , Kotla\u0301r\u030cska\u0301 267\/2 , ,","place":["Brno, Czech Republic, 611 37"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2021,2,10]]},"reference":[{"key":"2026092806084114800_cit1","doi-asserted-by":"publisher","first-page":"11714","DOI":"10.1039\/C2SM26008E","article-title":"Homo-polymers\nwith balanced hydrophobicity\ntranslocate through lipid bilayers and enhance local solvent permeability","volume":"8","author":"Werner","year":"2012","journal-title":"Soft Matter"},{"key":"2026092806084114800_cit2","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1042\/bj20061100","article-title":"Cell-penetrating\npeptides and antimicrobial\npeptides: how different are they?","volume":"399","author":"Henriques","year":"2006","journal-title":"Biochem.\nJ."},{"key":"2026092806084114800_cit3","doi-asserted-by":"publisher","first-page":"76","DOI":"10.2174\/1568026615666150703121009","article-title":"Non-Membrane\nPermeabilizing Modes of Action of Antimicrobial Peptides on Bacteria","volume":"16","author":"Scocchi","year":"2016","journal-title":"Curr. Top. Med. Chem."},{"key":"2026092806084114800_cit4","doi-asserted-by":"publisher","first-page":"529","DOI":"10.1016\/j.addr.2004.10.010","article-title":"Cell-penetrating peptides:\nmechanism and kinetics of\ncargo delivery","volume":"57","author":"Zorko","year":"2005","journal-title":"Adv. Drug Delivery Rev."},{"key":"2026092806084114800_cit5","doi-asserted-by":"publisher","first-page":"750","DOI":"10.1021\/bc050283q","article-title":"Evaluation\nof Cell-Penetrating Peptides (CPPs) as Vehicles\nfor Intracellular Delivery of Antisense Peptide Nucleic Acid (PNA)","volume":"17","author":"Bendifallah","year":"2006","journal-title":"Bioconjugate Chem."},{"key":"2026092806084114800_cit6","doi-asserted-by":"publisher","first-page":"95","DOI":"10.1038\/mt.2008.215","article-title":"A New Potent Secondary\nAmphipathic Cell\u2013penetrating Peptide for siRNA Delivery Into\nMammalian Cells","volume":"17","author":"Crombez","year":"2009","journal-title":"Mol. Ther."},{"key":"2026092806084114800_cit7","doi-asserted-by":"publisher","first-page":"8083","DOI":"10.1021\/bi900914g","article-title":"Mechanisms of antimicrobial, cytolytic, and cell-penetrating\npeptides: from kinetics to thermodynamics","volume":"48","author":"Almeida","year":"2009","journal-title":"Biochemistry"},{"key":"2026092806084114800_cit8","doi-asserted-by":"publisher","first-page":"2434","DOI":"10.1529\/biophysj.106.100198","article-title":"Mechanism of the cell-penetrating\npeptide transportan 10 permeation of lipid bilayers","volume":"92","author":"Yandek","year":"2007","journal-title":"Biophys. J."},{"key":"2026092806084114800_cit9","doi-asserted-by":"publisher","first-page":"842","DOI":"10.1038\/nsb1096-842","article-title":"Experimentally determined\nhydrophobicity scale for\nproteins at membrane interfaces","volume":"3","author":"Wimley","year":"1996","journal-title":"Nat. Struct.\nBiol."},{"key":"2026092806084114800_cit10","doi-asserted-by":"publisher","first-page":"4175","DOI":"10.1021\/ct200316w","article-title":"Statistical\nConvergence of Equilibrium Properties in Simulations of Molecular\nSolutes Embedded in Lipid Bilayers","volume":"7","author":"Neale","year":"2011","journal-title":"J. Chem.\nTheory Comput."},{"key":"2026092806084114800_cit11","doi-asserted-by":"publisher","first-page":"1200","DOI":"10.1021\/ct2009208","article-title":"Convergence of Free Energy Profile\nof Coumarin in Lipid Bilayer","volume":"8","author":"Paloncy\u0301ova\u0301","year":"2012","journal-title":"J. Chem. Theory\nComput."},{"key":"2026092806084114800_cit12","doi-asserted-by":"publisher","first-page":"1781","DOI":"10.1021\/jz4007993","article-title":"Exploring\nthe Free Energy Landscape\nof Solutes Embedded in Lipid Bilayers","volume":"4","author":"Ja\u0308mbeck","year":"2013","journal-title":"J. Phys.\nChem. 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Theory Comput."},{"key":"2026092806084114800_cit19","doi-asserted-by":"publisher","first-page":"700","DOI":"10.1021\/acs.jctc.9b00671","article-title":"Free Energy Calculations\non the Water-Chain-Assisted\nand the Dehydration Mechanisms of Transmembrane Ion Permeation","volume":"16","author":"Guan","year":"2020","journal-title":"J. Chem. Theory Comput."},{"key":"2026092806084114800_cit20","doi-asserted-by":"publisher","first-page":"253","DOI":"10.1006\/bbrc.1998.8159","article-title":"Mechanism\nof action of the antimicrobial\npeptide buforin II: buforin II kills microorganisms by penetrating\nthe cell membrane and inhibiting cellular functions","volume":"244","author":"Park","year":"1998","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"2026092806084114800_cit21","doi-asserted-by":"publisher","first-page":"19","DOI":"10.1016\/j.softx.2015.06.001","article-title":"GROMACS: High performance\nmolecular simulations through multi-level parallelism from laptops\nto supercomputers","volume":"1\u20132","author":"Abraham","year":"2015","journal-title":"SoftwareX"},{"key":"2026092806084114800_cit22","first-page":"3","volume-title":"Lecture Notes in Computer\nScience","author":"Pa\u0301ll","year":"2015"},{"key":"2026092806084114800_cit23","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":"Comput.\nPhys. 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Theory Comput."},{"key":"2026092806084114800_cit27","doi-asserted-by":"publisher","first-page":"014101","DOI":"10.1063\/1.2408420","article-title":"Canonical sampling through velocity\nrescaling","volume":"126","author":"Bussi","year":"2007","journal-title":"J. Chem. Phys."},{"key":"2026092806084114800_cit28","doi-asserted-by":"publisher","first-page":"1196","DOI":"10.1103\/physrevlett.45.1196","article-title":"Crystal Structure\nand Pair Potentials: A Molecular-Dynamics\nStudy","volume":"45","author":"Parrinello","year":"1980","journal-title":"Phys. Rev. Lett."},{"key":"2026092806084114800_cit29","doi-asserted-by":"publisher","first-page":"7182","DOI":"10.1063\/1.328693","article-title":"Polymorphic transitions in single\ncrystals: A new molecular\ndynamics method","volume":"52","author":"Parrinello","year":"1981","journal-title":"J. Appl. Phys."},{"key":"2026092806084114800_cit30","doi-asserted-by":"publisher","DOI":"10.7554\/elife.47946","article-title":"Effect of\nhelical kink in antimicrobial peptides on membrane pore formation","volume":"9","author":"Tuerkova","year":"2020","journal-title":"eLife"},{"key":"2026092806084114800_cit31","doi-asserted-by":"publisher","first-page":"391","DOI":"10.1016\/s0304-4157(98)00014-8","article-title":"Magainins\nas paradigm for the mode of action of pore forming polypeptides","volume":"1376","author":"Matsuzaki","year":"1998","journal-title":"Biochim. Biophys. Acta, Rev. Biomembr."},{"key":"2026092806084114800_cit32","doi-asserted-by":"publisher","first-page":"1859","DOI":"10.1002\/jcc.20945","article-title":"CHARMM-GUI: A web-based\ngraphical\nuser interface for CHARMM","volume":"29","author":"Jo","year":"2008","journal-title":"J. Comput. Chem."},{"key":"2026092806084114800_cit33","doi-asserted-by":"publisher","first-page":"5940","DOI":"10.1021\/acs.jpcb.0c03291","article-title":"Effect of Helical Kink on Peptide\nTranslocation across Phospholipid Membranes","volume":"124","author":"Broz\u030cek","year":"2020","journal-title":"J. Phys. Chem. B"},{"key":"2026092806084114800_cit34","doi-asserted-by":"publisher","first-page":"12562","DOI":"10.1073\/pnas.202427399","article-title":"Escaping free-energy\nminima","volume":"99","author":"Laio","year":"2002","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"2026092806084114800_cit35","doi-asserted-by":"publisher","first-page":"134101","DOI":"10.1063\/1.2844595","article-title":"Adaptively biased molecular\ndynamics\nfor free energy calculations","volume":"128","author":"Babin","year":"2008","journal-title":"J. Chem. Phys."},{"key":"2026092806084114800_cit36","doi-asserted-by":"publisher","first-page":"3533","DOI":"10.1021\/jp054359r","article-title":"Efficient reconstruction of complex free energy landscapes\nby multiple walkers metadynamics","volume":"110","author":"Raiteri","year":"2006","journal-title":"J. Phys. Chem.\nB"},{"key":"2026092806084114800_cit37","doi-asserted-by":"publisher","first-page":"020603","DOI":"10.1103\/physrevlett.100.020603","article-title":"Well-Tempered\nMetadynamics: A Smoothly\nConverging and Tunable Free-Energy Method","volume":"100","author":"Barducci","year":"2008","journal-title":"Phys.\nRev. Lett."},{"key":"2026092806084114800_cit38","doi-asserted-by":"crossref","unstructured":"Spiwok, V.\n          \n          metadynminer:\nTools to Read, Analyze and Visualize Metadynamics HILLS Files from\n\u2018Plumed\u2019. R package version 0.1.5, 2019.","DOI":"10.32614\/CRAN.package.metadynminer"},{"key":"2026092806084114800_cit39","doi-asserted-by":"publisher","first-page":"20785","DOI":"10.1039\/c4cp02211d","article-title":"Effect of arginine-rich\ncell penetrating peptides on membrane pore formation and life-times:\na molecular simulation study","volume":"16","author":"Sun","year":"2014","journal-title":"Phys. Chem. Chem.\nPhys."},{"key":"2026092806084114800_cit40","doi-asserted-by":"publisher","first-page":"3261","DOI":"10.1021\/acs.jctc.6b00369","article-title":"Simulations of Pore\nFormation in Lipid Membranes: Reaction\nCoordinates, Convergence, Hysteresis, and Finite-Size Effects","volume":"12","author":"Awasthi","year":"2016","journal-title":"J. Chem. Theory Comput."},{"key":"2026092806084114800_cit41","doi-asserted-by":"publisher","first-page":"3572","DOI":"10.1021\/jp501622d","article-title":"How To Tackle the Issues in Free Energy Simulations\nof Long Amphiphiles Interacting with Lipid Membranes: Convergence\nand Local Membrane Deformations","volume":"118","author":"Filipe","year":"2014","journal-title":"J. Phys. Chem.\nB"},{"key":"2026092806084114800_cit42","doi-asserted-by":"publisher","first-page":"3393","DOI":"10.1529\/biophysj.107.112805","article-title":"Distribution\nof Amino Acids in a\nLipid Bilayer from Computer Simulations","volume":"94","author":"MacCallum","year":"2008","journal-title":"Biophys.\nJ."}],"container-title":["Journal of Chemical Information and Modeling"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pubs.acs.org\/doi\/pdf\/10.1021\/acs.jcim.0c01312","content-type":"application\/pdf","content-version":"vor","intended-application":"unspecified"},{"URL":"https:\/\/pubs.acs.org\/jcisd8\/article-pdf\/61\/2\/819\/68674478\/acs.jcim.0c01312.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/pubs.acs.org\/jcisd8\/article-pdf\/61\/2\/819\/68674478\/acs.jcim.0c01312.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T10:30:22Z","timestamp":1790591422000},"score":1,"resource":{"primary":{"URL":"https:\/\/pubs.acs.org\/jcisd8\/article\/61\/2\/819\/849850\/Selecting-Collective-Variables-and-Free-Energy"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,2,10]]},"references-count":42,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2021,2,10]]},"published-print":{"date-parts":[[2021,2,22]]}},"URL":"https:\/\/doi.org\/10.1021\/acs.jcim.0c01312","relation":{},"ISSN":["1549-9596","1549-960X"],"issn-type":[{"value":"1549-9596","type":"print"},{"value":"1549-960X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,2,10]]}}}