{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,23]],"date-time":"2026-02-23T23:18:39Z","timestamp":1771888719318,"version":"3.50.1"},"reference-count":48,"publisher":"Springer Science and Business Media LLC","issue":"11","license":[{"start":{"date-parts":[[2020,8,27]],"date-time":"2020-08-27T00:00:00Z","timestamp":1598486400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.springer.com\/tdm"},{"start":{"date-parts":[[2020,8,27]],"date-time":"2020-08-27T00:00:00Z","timestamp":1598486400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.springer.com\/tdm"}],"funder":[{"DOI":"10.13039\/501100000275","name":"Leverhulme Trust","doi-asserted-by":"publisher","award":["RPG-2017-255"],"award-info":[{"award-number":["RPG-2017-255"]}],"id":[{"id":"10.13039\/501100000275","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["J Comput Aided Mol Des"],"published-print":{"date-parts":[[2020,11]]},"DOI":"10.1007\/s10822-020-00338-6","type":"journal-article","created":{"date-parts":[[2020,8,27]],"date-time":"2020-08-27T01:02:36Z","timestamp":1598490156000},"page":"1181-1193","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["Addressing free fatty acid receptor 1 (FFAR1) activation using supervised molecular dynamics"],"prefix":"10.1007","volume":"34","author":[{"given":"Silvia","family":"Atanasio","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8780-2986","authenticated-orcid":false,"given":"Giuseppe","family":"Deganutti","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9267-5141","authenticated-orcid":false,"given":"Christopher A.","family":"Reynolds","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2020,8,27]]},"reference":[{"key":"338_CR1","doi-asserted-by":"crossref","first-page":"406","DOI":"10.1016\/S0006-291X(02)03064-4","volume":"301","author":"K Kotarsky","year":"2003","unstructured":"Kotarsky K, Nilsson NE, Flodgren E et al (2003) A human cell surface receptor activated by free fatty acids and thiazolidinedione drugs. Biochem Biophys Res Commun 301:406\u2013410","journal-title":"Biochem Biophys Res Commun"},{"key":"338_CR2","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1038\/nature01478","volume":"422","author":"Y Itoh","year":"2003","unstructured":"Itoh Y, Kawamata Y, Harada M et al (2003) Free fatty acids regulate insulin secretion from pancreatic beta cells through GPR40. Nature 422:173\u2013176","journal-title":"Nature"},{"key":"338_CR3","doi-asserted-by":"crossref","first-page":"2280","DOI":"10.2337\/db08-0307","volume":"57","author":"S Edfalk","year":"2008","unstructured":"Edfalk S, Steneberg P, Edlund H (2008) Gpr40 is expressed in enteroendocrine cells and mediates free fatty acid stimulation of incretin secretion. Diabetes 57:2280\u20132287","journal-title":"Diabetes"},{"key":"338_CR4","unstructured":"World Health Organization (2016) Diabetes mellitus fact sheet. https:\/\/www.who.int\/news-room\/fact-sheets\/detail\/diabetes"},{"key":"338_CR5","doi-asserted-by":"crossref","first-page":"137","DOI":"10.3389\/fendo.2014.00137","volume":"5","author":"KR Watterson","year":"2014","unstructured":"Watterson KR, Hudson BD, Ulven T, Milligan G (2014) Treatment of type 2 diabetes by free fatty acid receptor agonists. Front Endocrinol (Lausanne) 5:137","journal-title":"Front Endocrinol (Lausanne)"},{"key":"338_CR6","doi-asserted-by":"crossref","first-page":"381","DOI":"10.1002\/med.21441","volume":"38","author":"Z Li","year":"2018","unstructured":"Li Z, Xu X, Huang W, Qian H (2018) Free fatty acid receptor 1 (FFAR1) as an emerging therapeutic target for type 2 diabetes mellitus: recent progress and prevailing challenges. Med Res Rev 38:381\u2013425","journal-title":"Med Res Rev"},{"key":"338_CR7","doi-asserted-by":"crossref","first-page":"1403","DOI":"10.1016\/S0140-6736(11)61879-5","volume":"379","author":"CF Burant","year":"2012","unstructured":"Burant CF, Viswanathan P, Marcinak J et al (2012) TAK-875 versus placebo or glimepiride in type 2 diabetes mellitus: a phase 2, randomised, double-blind, placebo-controlled trial. Lancet (London, England) 379:1403\u20131411","journal-title":"Lancet (London, England)"},{"key":"338_CR8","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1007\/164_2016_52","volume":"236","author":"IG Tikhonova","year":"2017","unstructured":"Tikhonova IG (2017) Application of GPCR structures for modelling of free fatty acid receptors. Handb Exp Pharmacol 236:57\u201377","journal-title":"Handb Exp Pharmacol"},{"key":"338_CR9","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1186\/s12900-015-0044-2","volume":"15","author":"IG Tikhonova","year":"2015","unstructured":"Tikhonova IG, Poerio E (2015) Free fatty acid receptors: structural models and elucidation of ligand binding interactions. BMC Struct Biol 15:16","journal-title":"BMC Struct Biol"},{"key":"338_CR10","doi-asserted-by":"crossref","first-page":"1645","DOI":"10.1038\/s41467-017-01240-w","volume":"9","author":"JD Ho","year":"2018","unstructured":"Ho JD, Chau B, Rodgers L et al (2018) Structural basis for GPR40 allosteric agonism and incretin stimulation. Nat Commun 9:1645","journal-title":"Nat Commun"},{"key":"338_CR11","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1021\/acs.chemrev.6b00177","volume":"117","author":"NR Latorraca","year":"2017","unstructured":"Latorraca NR, Venkatakrishnan AJ, Dror RO (2017) GPCR dynamics: structures in motion. Chem Rev 117:139\u2013155","journal-title":"Chem Rev"},{"key":"338_CR12","doi-asserted-by":"crossref","first-page":"897","DOI":"10.1146\/annurev-biochem-060614-033910","volume":"87","author":"WI Weis","year":"2018","unstructured":"Weis WI, Kobilka BK (2018) The molecular basis of G protein-coupled receptor activation. Annu Rev Biochem 87:897\u2013919","journal-title":"Annu Rev Biochem"},{"key":"338_CR13","doi-asserted-by":"crossref","first-page":"843","DOI":"10.1124\/mol.112.079640","volume":"82","author":"DCH Lin","year":"2012","unstructured":"Lin DCH, Guo Q, Luo J et al (2012) Identification and pharmacological characterization of multiple allosteric binding sites on the free fatty acid 1 receptor. Mol Pharmacol 82:843\u2013859","journal-title":"Mol Pharmacol"},{"key":"338_CR14","doi-asserted-by":"crossref","first-page":"e76280","DOI":"10.1371\/journal.pone.0076280","volume":"8","author":"C Yabuki","year":"2013","unstructured":"Yabuki C, Komatsu H, Tsujihata Y et al (2013) A novel antidiabetic drug, fasiglifam\/TAK-875, acts as an ago-allosteric modulator of FFAR1. PLoS ONE 8:e76280","journal-title":"PLoS ONE"},{"key":"338_CR15","doi-asserted-by":"crossref","first-page":"124","DOI":"10.1038\/nature13494","volume":"513","author":"A Srivastava","year":"2014","unstructured":"Srivastava A, Yano J, Hirozane Y et al (2014) High-resolution structure of the human GPR40 receptor bound to allosteric agonist TAK-875. Nature 513:124\u2013127","journal-title":"Nature"},{"key":"338_CR16","doi-asserted-by":"crossref","first-page":"3529","DOI":"10.1074\/jbc.M806987200","volume":"284","author":"CS Sum","year":"2009","unstructured":"Sum CS, Tikhonova IG, Costanzi S, Gershengorn MC (2009) Two arginine-glutamate ionic locks near the extracellular surface of FFAR1 gate receptor activation. J Biol Chem 284:3529\u20133536","journal-title":"J Biol Chem"},{"key":"338_CR17","doi-asserted-by":"crossref","first-page":"570","DOI":"10.1038\/nsmb.3417","volume":"24","author":"J Lu","year":"2017","unstructured":"Lu J, Byrne N, Wang J et al (2017) Structural basis for the cooperative allosteric activation of the free fatty acid receptor GPR40. Nat Struct Mol Biol 24:570\u2013577","journal-title":"Nat Struct Mol Biol"},{"key":"338_CR18","doi-asserted-by":"crossref","first-page":"7123","DOI":"10.1073\/pnas.1811066116","volume":"116","author":"M L\u00fcckmann","year":"2019","unstructured":"L\u00fcckmann M, Trauelsen M, Bentsen MA et al (2019) Molecular dynamics-guided discovery of an ago-allosteric modulator for GPR40\/FFAR1. Proc Natl Acad Sci U S A 116:7123\u20137128","journal-title":"Proc Natl Acad Sci U S A"},{"key":"338_CR19","doi-asserted-by":"crossref","first-page":"22639","DOI":"10.1038\/srep22639","volume":"6","author":"N Stanley","year":"2016","unstructured":"Stanley N, Pardo L, De FG (2016) The pathway of ligand entry from the membrane bilayer to a lipid G protein-coupled receptor. Sci Rep 6:22639","journal-title":"Sci Rep"},{"key":"338_CR20","doi-asserted-by":"crossref","first-page":"2457","DOI":"10.1021\/acs.jcim.6b00499","volume":"56","author":"J Jakowiecki","year":"2016","unstructured":"Jakowiecki J, Filipek S (2016) Hydrophobic ligand entry and exit pathways of the CB1 cannabinoid receptor. J Chem Inf Model 56:2457\u20132466","journal-title":"J Chem Inf Model"},{"key":"338_CR21","doi-asserted-by":"crossref","first-page":"D356","DOI":"10.1093\/nar\/gkv1178","volume":"44","author":"V Isberg","year":"2016","unstructured":"Isberg V, Mordalski S, Munk C et al (2016) GPCRdb: an information system for G protein-coupled receptors. Nucleic Acids Res 44:D356\u2013D364","journal-title":"Nucleic Acids Res"},{"key":"338_CR22","doi-asserted-by":"crossref","first-page":"1845","DOI":"10.1021\/acs.jctc.6b00049","volume":"12","author":"S Doerr","year":"2016","unstructured":"Doerr S, Harvey MJ, No\u00e9 F, De Fabritiis G (2016) HTMD: high-throughput molecular dynamics for molecular discovery. J Chem Theory Comput 12:1845\u20131852","journal-title":"J Chem Theory Comput"},{"key":"338_CR23","doi-asserted-by":"crossref","first-page":"623","DOI":"10.1093\/bioinformatics\/btk023","volume":"22","author":"MA Lomize","year":"2006","unstructured":"Lomize MA, Lomize AL, Pogozheva ID, Mosberg HI (2006) OPM: orientations of proteins in membranes database. Bioinformatics 22:623\u2013625","journal-title":"Bioinformatics"},{"key":"338_CR24","doi-asserted-by":"crossref","first-page":"W665","DOI":"10.1093\/nar\/gkh381","volume":"32","author":"TJ Dolinsky","year":"2004","unstructured":"Dolinsky TJ, Nielsen JE, McCammon JA, Baker NA (2004) PDB2PQR: an automated pipeline for the setup of Poisson\u2013Boltzmann electrostatics calculations. Nucleic Acids Res 32:W665\u2013W667","journal-title":"Nucleic Acids Res"},{"key":"338_CR25","doi-asserted-by":"crossref","first-page":"525","DOI":"10.1021\/ct100578z","volume":"7","author":"MHM Olsson","year":"2011","unstructured":"Olsson MHM, S\u00f8ndergaard CR, Rostkowski M, Jensen JH (2011) PROPKA3: consistent treatment of internal and surface residues in empirical pKa predictions. J Chem Theory Comput 7:525\u2013537","journal-title":"J Chem Theory Comput"},{"key":"338_CR26","doi-asserted-by":"crossref","first-page":"e201302014","DOI":"10.5936\/csbj.201302014","volume":"5","author":"B Sommer","year":"2013","unstructured":"Sommer B (2013) Membrane packing problems: a short review on computational membrane modeling methods and tools. Comput Struct Biotechnol J 5:e201302014","journal-title":"Comput Struct Biotechnol J"},{"key":"338_CR27","doi-asserted-by":"crossref","first-page":"1632","DOI":"10.1021\/ct9000685","volume":"5","author":"MJ Harvey","year":"2009","unstructured":"Harvey MJ, Giupponi G, De FG (2009) ACEMD: accelerating biomolecular dynamics in the microsecond time scale. J Chem Theory Comput 5:1632\u20131639","journal-title":"J Chem Theory Comput"},{"key":"338_CR28","doi-asserted-by":"crossref","first-page":"7830","DOI":"10.1021\/jp101759q","volume":"114","author":"JB Klauda","year":"2010","unstructured":"Klauda JB, Venable RM, Freites JA et al (2010) Update of the CHARMM all-atom additive force field for lipids: validation on six lipid types. J Phys Chem B 114:7830\u20137843","journal-title":"J Phys Chem B"},{"key":"338_CR29","doi-asserted-by":"crossref","first-page":"2135","DOI":"10.1002\/jcc.23354","volume":"34","author":"J Huang","year":"2013","unstructured":"Huang J, MacKerell AD (2013) CHARMM36 all-atom additive protein force field: validation based on comparison to NMR data. J Comput Chem 34:2135\u20132145","journal-title":"J Comput Chem"},{"key":"338_CR30","doi-asserted-by":"crossref","first-page":"671","DOI":"10.1002\/jcc.21367","volume":"31","author":"K Vanommeslaeghe","year":"2010","unstructured":"Vanommeslaeghe K, Hatcher E, Acharya C et al (2010) CHARMM general force field: a force field for drug-like molecules compatible with the CHARMM all-atom additive biological force fields. J Comput Chem 31:671\u2013690","journal-title":"J Comput Chem"},{"key":"338_CR31","doi-asserted-by":"crossref","first-page":"2757","DOI":"10.1002\/jcc.23422","volume":"34","author":"CG Mayne","year":"2013","unstructured":"Mayne CG, Saam J, Schulten K et al (2013) Rapid parameterization of small molecules using the Force Field Toolkit. J Comput Chem 34:2757\u20132770","journal-title":"J Comput Chem"},{"key":"338_CR32","doi-asserted-by":"crossref","first-page":"523","DOI":"10.1002\/bip.360320508","volume":"32","author":"RJ Loncharich","year":"1992","unstructured":"Loncharich RJ, Brooks BR, Pastor RW (1992) Langevin dynamics of peptides: the frictional dependence of isomerization rates of N-acetylalanyl-N\u2032-methylamide. Biopolymers 32:523\u2013535","journal-title":"Biopolymers"},{"key":"338_CR33","doi-asserted-by":"crossref","first-page":"3684","DOI":"10.1063\/1.448118","volume":"81","author":"HJC Berendsen","year":"1984","unstructured":"Berendsen HJC, Postma JPM, van Gunsteren WF et al (1984) Molecular dynamics with coupling to an external bath. J Chem Phys 81:3684\u20133690","journal-title":"J Chem Phys"},{"key":"338_CR34","doi-asserted-by":"crossref","first-page":"501","DOI":"10.1002\/1096-987X(20010415)22:5<501::AID-JCC1021>3.0.CO;2-V","volume":"22","author":"V Kr\u00e4utler","year":"2001","unstructured":"Kr\u00e4utler V, Van Gunsteren WF, H\u00fcnenberger PH (2001) A fast SHAKE algorithm to solve distance constraint equations for small molecules in molecular dynamics simulations. J Comput Chem 22:501\u2013508","journal-title":"J Comput Chem"},{"key":"338_CR35","doi-asserted-by":"crossref","first-page":"8577","DOI":"10.1063\/1.470117","volume":"103","author":"U Essmann","year":"1995","unstructured":"Essmann U, Perera L, Berkowitz ML et al (1995) A smooth particle mesh Ewald method. J Chem Phys 103:8577\u20138593","journal-title":"J Chem Phys"},{"key":"338_CR36","doi-asserted-by":"crossref","first-page":"372","DOI":"10.1021\/ci400766b","volume":"54","author":"D Sabbadin","year":"2014","unstructured":"Sabbadin D, Moro S (2014) Supervised molecular dynamics (SuMD) as a helpful tool to depict GPCR-ligand recognition pathway in a nanosecond time scale. J Chem Inf Model 54:372\u2013376","journal-title":"J Chem Inf Model"},{"key":"338_CR37","doi-asserted-by":"crossref","first-page":"687","DOI":"10.1021\/acs.jcim.5b00702","volume":"56","author":"A Cuzzolin","year":"2016","unstructured":"Cuzzolin A, Sturlese M, Deganutti G et al (2016) Deciphering the complexity of ligand-protein recognition pathways using supervised molecular dynamics (SuMD) simulations. J Chem Inf Model 56:687\u2013705","journal-title":"J Chem Inf Model"},{"key":"338_CR38","doi-asserted-by":"crossref","first-page":"1804","DOI":"10.1021\/acs.jcim.9b01094","volume":"60","author":"G Deganutti","year":"2020","unstructured":"Deganutti G, Moro S, Reynolds CA (2020) A supervised molecular dynamics approach to unbiased ligand-protein unbinding. J Chem Inf Model 60:1804\u20131817","journal-title":"J Chem Inf Model"},{"key":"338_CR39","doi-asserted-by":"crossref","first-page":"604","DOI":"10.1016\/j.cpc.2013.09.018","volume":"185","author":"GA Tribello","year":"2014","unstructured":"Tribello GA, Bonomi M, Branduardi D et al (2014) PLUMED 2: new feathers for an old bird. Comput Phys Commun 185:604\u2013613","journal-title":"Comput Phys Commun"},{"issue":"33\u20138","key":"338_CR40","first-page":"27","volume":"14","author":"W Humphrey","year":"1996","unstructured":"Humphrey W, Dalke A, Schulten K (1996) VMD: visual molecular dynamics. J Mol Graph 14(33\u20138):27\u201328","journal-title":"J Mol Graph"},{"key":"338_CR41","doi-asserted-by":"crossref","first-page":"3314","DOI":"10.1021\/ct300418h","volume":"8","author":"BR Miller","year":"2012","unstructured":"Miller BR, McGee TD, Swails JM et al (2012) MMPBSA.py: an efficient program for end-state free energy calculations. J Chem Theory Comput 8:3314\u20133321","journal-title":"J Chem Theory Comput"},{"key":"338_CR42","doi-asserted-by":"crossref","first-page":"449","DOI":"10.1517\/17460441.2015.1032936","volume":"10","author":"S Genheden","year":"2015","unstructured":"Genheden S, Ryde U (2015) The MM\/PBSA and MM\/GBSA methods to estimate ligand-binding affinities. Expert Opin Drug Discov 10:449\u2013461","journal-title":"Expert Opin Drug Discov"},{"key":"338_CR43","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1016\/j.tips.2014.11.001","volume":"36","author":"V Isberg","year":"2015","unstructured":"Isberg V, de Graaf C, Bortolato A et al (2015) Generic GPCR residue numbers\u2014aligning topology maps while minding the gaps. Trends Pharmacol Sci 36:22\u201331","journal-title":"Trends Pharmacol Sci"},{"key":"338_CR44","doi-asserted-by":"crossref","first-page":"233","DOI":"10.1016\/j.tibs.2014.03.002","volume":"39","author":"V Katritch","year":"2014","unstructured":"Katritch V, Fenalti G, Abola EE et al (2014) Allosteric sodium in class A GPCR signaling. Trends Biochem Sci 39:233\u2013244","journal-title":"Trends Biochem Sci"},{"key":"338_CR45","doi-asserted-by":"crossref","first-page":"1688","DOI":"10.1111\/j.1476-5381.2011.01629.x","volume":"165","author":"M Wheatley","year":"2012","unstructured":"Wheatley M, Wootten D, Conner MT et al (2012) Lifting the lid on GPCRs: the role of extracellular loops. Br J Pharmacol 165:1688\u20131703","journal-title":"Br J Pharmacol"},{"key":"338_CR46","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1016\/j.tips.2010.10.001","volume":"32","author":"MC Peeters","year":"2011","unstructured":"Peeters MC, van Westen GJP, Li Q, Ijzerman AP (2011) Importance of the extracellular loops in G protein-coupled receptors for ligand recognition and receptor activation. Trends Pharmacol Sci 32:35\u201342","journal-title":"Trends Pharmacol Sci"},{"key":"338_CR47","doi-asserted-by":"crossref","first-page":"21131","DOI":"10.1074\/jbc.M115.644450","volume":"290","author":"AD Mancini","year":"2015","unstructured":"Mancini AD, Bertrand G, Vivot K et al (2015) \u03b2-Arrestin recruitment and biased agonism at free fatty acid receptor 1. J Biol Chem 290:21131\u201321140","journal-title":"J Biol Chem"},{"key":"338_CR48","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jcim.0c00030","author":"D Teng","year":"2020","unstructured":"Teng D, Chen J, Li D et al (2020) Computational insights into molecular activation and positive cooperative mechanisms of FFAR1 modulators. J Chem Inf Model. https:\/\/doi.org\/10.1021\/acs.jcim.0c00030","journal-title":"J Chem Inf Model"}],"container-title":["Journal of Computer-Aided Molecular Design"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s10822-020-00338-6.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s10822-020-00338-6\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s10822-020-00338-6.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,8,12]],"date-time":"2024-08-12T16:29:01Z","timestamp":1723480141000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s10822-020-00338-6"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,8,27]]},"references-count":48,"journal-issue":{"issue":"11","published-print":{"date-parts":[[2020,11]]}},"alternative-id":["338"],"URL":"https:\/\/doi.org\/10.1007\/s10822-020-00338-6","relation":{},"ISSN":["0920-654X","1573-4951"],"issn-type":[{"value":"0920-654X","type":"print"},{"value":"1573-4951","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,8,27]]},"assertion":[{"value":"14 May 2020","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"18 August 2020","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"27 August 2020","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}}]}}