{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,15]],"date-time":"2025-10-15T10:06:41Z","timestamp":1760522801665},"reference-count":39,"publisher":"Springer Science and Business Media LLC","issue":"1","content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["BMC Bioinformatics"],"published-print":{"date-parts":[[2010,12]]},"abstract":"<jats:title>Abstract<\/jats:title>\n          <jats:sec>\n            <jats:title>Background<\/jats:title>\n            <jats:p>An adaptive coarse-grained (kinetic) Monte Carlo (ACGMC) simulation framework is applied to reaction and diffusion dynamics in inhomogeneous domains. The presented model is relevant to the diffusion and dimerization dynamics of epidermal growth factor receptor (EGFR) in the presence of plasma membrane heterogeneity and specifically receptor clustering. We perform simulations representing EGFR cluster dissipation in heterogeneous plasma membranes consisting of higher density clusters of receptors surrounded by low population areas using the ACGMC method. We further investigate the effect of key parameters on the cluster lifetime.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Results<\/jats:title>\n            <jats:p>Coarse-graining of dimerization, rather than of diffusion, may lead to computational error. It is shown that the ACGMC method is an effective technique to minimize error in diffusion-reaction processes and is superior to the microscopic kinetic Monte Carlo simulation in terms of computational cost while retaining accuracy. The low computational cost enables sensitivity analysis calculations. Sensitivity analysis indicates that it may be possible to retain clusters of receptors over the time scale of minutes under suitable conditions and the cluster lifetime may depend on both receptor density and cluster size.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions<\/jats:title>\n            <jats:p>The ACGMC method is an ideal platform to resolve large length and time scales in heterogeneous biological systems well beyond the plasma membrane and the EGFR system studied here. Our results demonstrate that cluster size must be considered in conjunction with receptor density, as they synergistically affect EGFR cluster lifetime. Further, the cluster lifetime being of the order of several seconds suggests that any mechanisms responsible for EGFR aggregation must operate on shorter timescales (at most a fraction of a second), to overcome dissipation and produce stable clusters observed experimentally.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1186\/1471-2105-11-218","type":"journal-article","created":{"date-parts":[[2010,4,29]],"date-time":"2010-04-29T18:15:53Z","timestamp":1272564953000},"update-policy":"http:\/\/dx.doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Adaptive coarse-grained Monte Carlo simulation of reaction and diffusion dynamics in heterogeneous plasma membranes"],"prefix":"10.1186","volume":"11","author":[{"given":"Stuart","family":"Collins","sequence":"first","affiliation":[]},{"given":"Michail","family":"Stamatakis","sequence":"additional","affiliation":[]},{"given":"Dionisios G","family":"Vlachos","sequence":"additional","affiliation":[]}],"member":"297","published-online":{"date-parts":[[2010,4,29]]},"reference":[{"key":"3675_CR1","doi-asserted-by":"publisher","first-page":"127","DOI":"10.1038\/35052073","volume":"2","author":"Y Yarden","year":"2001","unstructured":"Yarden Y, Sliwkowski MX: Untangling the ErbB signalling network. Nat Rev Mol Cell Bio 2001, 2: 127\u2013137. 10.1038\/35052073","journal-title":"Nat Rev Mol Cell Bio"},{"key":"3675_CR2","doi-asserted-by":"publisher","first-page":"4493","DOI":"10.1021\/bi00133a016","volume":"31","author":"F Canals","year":"1992","unstructured":"Canals F: Signal Transmission by Epidermal Growth-Factor Receptor - Coincidence of Activation and Dimerization. Biochemistry 1992, 31: 4493\u20134501. 10.1021\/bi00133a016","journal-title":"Biochemistry"},{"key":"3675_CR3","doi-asserted-by":"publisher","first-page":"649","DOI":"10.1016\/j.yexcr.2008.07.031","volume":"315","author":"R Bose","year":"2009","unstructured":"Bose R, Zhang XW: The ErbB kinase domain: Structural perspectives into kinase activation and inhibition. Exp Cell Res 2009, 315: 649\u2013658. 10.1016\/j.yexcr.2008.07.031","journal-title":"Exp Cell Res"},{"key":"3675_CR4","doi-asserted-by":"publisher","first-page":"507","DOI":"10.1016\/S1097-2765(03)00047-9","volume":"11","author":"KM Ferguson","year":"2003","unstructured":"Ferguson KM, Berger MB, Mendrola JM, Cho H-S, Leahy DJ, Lemmon MA: EGF Activates Its Receptor by Removing Interactions that Autoinhibit Ectodomain Dimerization. Mol Cell 2003, 11: 507\u2013517. 10.1016\/S1097-2765(03)00047-9","journal-title":"Mol Cell"},{"key":"3675_CR5","doi-asserted-by":"publisher","first-page":"382","DOI":"10.1083\/jcb.81.2.382","volume":"81","author":"HT Haigler","year":"1979","unstructured":"Haigler HT, McKanna JA, Cohen S: Direct visualization of the binding and internalization of a ferritin conjugate of epidermal growth factor in human carcinoma cells A-431. J Cell Biol 1979, 81: 382\u2013395. 10.1083\/jcb.81.2.382","journal-title":"J Cell Biol"},{"key":"3675_CR6","first-page":"A824","volume":"19","author":"CL Howe","year":"2005","unstructured":"Howe CL: Modeling the signaling endosome hypothesis: Why a drive to the nucleus is better than a random walk. Faseb J 2005, 19: A824-A824.","journal-title":"Faseb J"},{"key":"3675_CR7","doi-asserted-by":"publisher","first-page":"2073","DOI":"10.1242\/jeb.00298","volume":"206","author":"BN Kholodenko","year":"2003","unstructured":"Kholodenko BN: Four-dimensional organization of protein kinase signaling cascades: the roles of diffusion, endocytosis and molecular motors. J Exp Biol 2003, 206: 2073\u20132082. 10.1242\/jeb.00298","journal-title":"J Exp Biol"},{"key":"3675_CR8","doi-asserted-by":"publisher","first-page":"2763","DOI":"10.1242\/jcs.007658","volume":"120","author":"S Yang","year":"2007","unstructured":"Yang S, Raymond-Stintz MA, Ying W, Zhang J, Lidke DS, Steinberg SL, Williams L, Oliver JM, Wilson BS: Mapping ErbB receptors on breast cancer cell membranes during signal transduction. J Cell Sci 2007, 120: 2763\u20132773. 10.1242\/jcs.007658","journal-title":"J Cell Sci"},{"key":"3675_CR9","doi-asserted-by":"publisher","first-page":"351","DOI":"10.1146\/annurev.biophys.34.040204.144637","volume":"34","author":"A Kusumi","year":"2005","unstructured":"Kusumi A, Nakada C, Ritchie K, Murase K, Suzuki K, Murakoshi H, Kasai RS, Kondo J, Fujiwara T: Paradigm shift of the plasma membrane concept from the two-dimensional continuum fluid to the partitioned fluid: High-speed single-molecule tracking of membrane molecules. Annu Rev Biophys Biomol Struct 2005, 34: 351-U354. 10.1146\/annurev.biophys.34.040204.144637","journal-title":"Annu Rev Biophys Biomol Struct"},{"key":"3675_CR10","doi-asserted-by":"publisher","first-page":"566","DOI":"10.1016\/S0955-0674(96)80036-6","volume":"8","author":"A Kusumi","year":"1996","unstructured":"Kusumi A, Sako Y: Cell surface organization by the membrane skeleton. Current Opinion in Cell Biology 1996, 8: 566\u2013574. 10.1016\/S0955-0674(96)80036-6","journal-title":"Current Opinion in Cell Biology"},{"key":"3675_CR11","first-page":"245","volume-title":"Meth Mol Biol, Biomedical and Life Sciences","author":"BS Wilson","year":"2007","unstructured":"Wilson BS, Pfeiffer JR, Raymond-Stintz MA, Lidke D, Andrews N, Zhang J, Yin W, Steinberg S, Oliver JM: Exploring Membrane Domains Using Native Membrane Sheets and Transmission Electron Microscopy. In Meth Mol Biol, Biomedical and Life Sciences. Volume 398. Edited by: McIntosh TJ. Humana Press; 2007:245\u2013261."},{"key":"3675_CR12","doi-asserted-by":"publisher","first-page":"851","DOI":"10.1083\/jcb.200606007","volume":"174","author":"N Morone","year":"2006","unstructured":"Morone N, Fujiwara T, Murase K, Kasai RS, Ike H, Yuasa S, Usukura J, Kusumi A: Three-dimensional reconstruction of the membrane skeleton at the plasma membrane interface by electron tomography. J Cell Biol 2006, 174: 851\u2013862. 10.1083\/jcb.200606007","journal-title":"J Cell Biol"},{"key":"3675_CR13","doi-asserted-by":"publisher","first-page":"655","DOI":"10.1194\/jlr.R200021-JLR200","volume":"44","author":"LJ Pike","year":"2003","unstructured":"Pike LJ: Lipid rafts: bringing order to chaos. The Journal of Lipid Research 2003, 44: 655\u2013667. 10.1194\/jlr.R200021-JLR200","journal-title":"The Journal of Lipid Research"},{"key":"3675_CR14","doi-asserted-by":"publisher","first-page":"112","DOI":"10.1038\/nrm1571","volume":"6","author":"C Le Roy","year":"2005","unstructured":"Le Roy C, Wrana JL: Clathrin- and non-clathrin-mediated endocytic regulation of cell signalling. Nat Rev Mol Cell Bio 2005, 6: 112\u2013126. 10.1038\/nrm1571","journal-title":"Nat Rev Mol Cell Bio"},{"key":"3675_CR15","doi-asserted-by":"publisher","first-page":"2089","DOI":"10.1016\/j.cellsig.2006.05.015","volume":"18","author":"ES Henson","year":"2006","unstructured":"Henson ES, Gibson SB: Surviving cell death through epidermal growth factor (EGF) signal transduction pathways: Implications for cancer therapy. Cell Signalling 2006, 18: 2089\u20132097. 10.1016\/j.cellsig.2006.05.015","journal-title":"Cell Signalling"},{"key":"3675_CR16","doi-asserted-by":"publisher","first-page":"908","DOI":"10.1038\/35103078","volume":"2","author":"JJ Tyson","year":"2001","unstructured":"Tyson JJ, Chen K, Novak B: Network dynamics and cell physiology. Nat Rev Mol Cell Bio 2001, 2: 908\u2013916. 10.1038\/35103078","journal-title":"Nat Rev Mol Cell Bio"},{"key":"3675_CR17","doi-asserted-by":"publisher","first-page":"2358","DOI":"10.1016\/S0006-3495(99)77073-6","volume":"77","author":"CL Guo","year":"1999","unstructured":"Guo CL, Levine H: A thermodynamic model for receptor clustering. Biophys J 1999, 77: 2358\u20132365. 10.1016\/S0006-3495(99)77073-6","journal-title":"Biophys J"},{"key":"3675_CR18","doi-asserted-by":"publisher","first-page":"199","DOI":"10.1016\/S0378-4371(02)00834-8","volume":"311","author":"Y Shi","year":"2002","unstructured":"Shi Y: Clustering and signalling of cell receptors. Physica A 2002, 311: 199\u2013212. 10.1016\/S0378-4371(02)00834-8","journal-title":"Physica A"},{"key":"3675_CR19","doi-asserted-by":"publisher","first-page":"41","DOI":"10.1186\/1471-2121-6-41","volume":"6","author":"K Mayawala","year":"2005","unstructured":"Mayawala K, Vlachos DG, Edwards JS: Computational modeling reveals molecular details of epidermal growth factor binding. BMC Cell Biol 2005, 6: 41. 10.1186\/1471-2121-6-41","journal-title":"BMC Cell Biol"},{"key":"3675_CR20","doi-asserted-by":"publisher","first-page":"125","DOI":"10.1016\/S0006-3495(00)76579-9","volume":"78","author":"DM Leitner","year":"2000","unstructured":"Leitner DM, Brown FLH, Wilson KR: Regulation of protein mobility in cell membranes: A dynamic corral model. Biophys J 2000, 78: 125\u2013135. 10.1016\/S0006-3495(00)76579-9","journal-title":"Biophys J"},{"key":"3675_CR21","doi-asserted-by":"publisher","first-page":"1551","DOI":"10.1529\/biophysj.107.106484","volume":"94","author":"AMS Niehaus","year":"2008","unstructured":"Niehaus AMS, Vlachos DG, Edwards JS, Plechac P, Tribe R: Microscopic Simulation of Membrane Molecule Diffusion on Corralled Membrane Surfaces. Biophys J 2008, 94: 1551\u20131564. 10.1529\/biophysj.107.106484","journal-title":"Biophys J"},{"key":"3675_CR22","doi-asserted-by":"crossref","first-page":"11083","DOI":"10.1016\/S0021-9258(18)99131-3","volume":"266","author":"HS Wiley","year":"1991","unstructured":"Wiley HS, Herbst JJ, Walsh BJ, Lauffenburger DA, Rosenfeld MG, Gill GN: The Role of Tyrosine Kinase-Activity in Endocytosis, Compartmentation, and down-Regulation of the Epidermal Growth-Factor Receptor. J Biol Chem 1991, 266: 11083\u201311094.","journal-title":"J Biol Chem"},{"key":"3675_CR23","doi-asserted-by":"publisher","first-page":"47","DOI":"10.1083\/jcb.129.1.47","volume":"129","author":"C Lamaze","year":"1995","unstructured":"Lamaze C, Schmid SL: Recruitment of Epidermal Growth-Factor Receptors into Coated Pits Requires Their Activated Tyrosine Kinase. J Cell Biol 1995, 129: 47\u201354. 10.1083\/jcb.129.1.47","journal-title":"J Cell Biol"},{"key":"3675_CR24","doi-asserted-by":"publisher","first-page":"27433","DOI":"10.1074\/jbc.M201595200","volume":"277","author":"T Sorkina","year":"2002","unstructured":"Sorkina T, Huang FT, Beguinot L, Sorkin A: Effect of tyrosine kinase inhibitors on clathrin-coated pit recruitment and internalization of epidermal growth factor receptor. J Biol Chem 2002, 277: 27433\u201327441. 10.1074\/jbc.M201595200","journal-title":"J Biol Chem"},{"key":"3675_CR25","doi-asserted-by":"publisher","first-page":"942","DOI":"10.1038\/sj.embor.7400491","volume":"6","author":"Q Wang","year":"2005","unstructured":"Wang Q, Villeneuve G, Wang ZX: Control of epidermal growth factor receptor endocytosis by receptor dimerization, rather than receptor kinase activation. Embo Rep 2005, 6: 942\u2013948. 10.1038\/sj.embor.7400491","journal-title":"Embo Rep"},{"key":"3675_CR26","doi-asserted-by":"publisher","first-page":"683","DOI":"10.1016\/j.yexcr.2008.07.029","volume":"315","author":"A Sorkin","year":"2009","unstructured":"Sorkin A, Goh LK: Endocytosis and intracellular trafficking of ErbBs. Exp Cell Res 2009, 315: 683\u2013696. 10.1016\/j.yexcr.2008.07.029","journal-title":"Exp Cell Res"},{"key":"3675_CR27","doi-asserted-by":"publisher","first-page":"1597","DOI":"10.1194\/jlr.E600002-JLR200","volume":"47","author":"LJ Pike","year":"2006","unstructured":"Pike LJ: Rafts defined: a report on the Keystone Symposium on Lipid Rafts and Cell Function. J Lipid Res 2006, 47: 1597\u20131598. 10.1194\/jlr.E600002-JLR200","journal-title":"J Lipid Res"},{"key":"3675_CR28","doi-asserted-by":"publisher","first-page":"250","DOI":"10.1016\/S0021-9991(03)00051-2","volume":"186","author":"MA Katsoulakis","year":"2003","unstructured":"Katsoulakis MA, Majda AJ, Vlachos DG: Coarse-grained stochastic processes and Monte Carlo simulations in lattice systems. J Comput Phys 2003, 186: 250\u2013278. 10.1016\/S0021-9991(03)00051-2","journal-title":"J Comput Phys"},{"key":"3675_CR29","doi-asserted-by":"publisher","first-page":"782","DOI":"10.1073\/pnas.242741499","volume":"100","author":"MA Katsoulakis","year":"2003","unstructured":"Katsoulakis MA, Majda AJ, Vlachos DG: Coarse-grained stochastic processes for microscopic lattice systems. Proc Nat Acad Sci USA 2003, 100: 782\u2013787. 10.1073\/pnas.242741499","journal-title":"Proc Nat Acad Sci USA"},{"key":"3675_CR30","doi-asserted-by":"publisher","first-page":"11420","DOI":"10.1063\/1.1811601","volume":"121","author":"A Chatterjee","year":"2004","unstructured":"Chatterjee A, Vlachos DG, Katsoulakis MA: Spatially adaptive lattice coarse-grained Monte Carlo simulations for diffusion of interacting molecules. J Chem Phys 2004, 121: 11420\u201311431. 10.1063\/1.1811601","journal-title":"J Chem Phys"},{"key":"3675_CR31","doi-asserted-by":"publisher","first-page":"026702","DOI":"10.1103\/PhysRevA.71.026702","volume":"71","author":"A Chatterjee","year":"2005","unstructured":"Chatterjee A, Katsoulakis MA, Vlachos DG: Spatially adaptive grand canonical ensemble Monte Carlo simulations. Phys Rev A 2005, 71: 026702. 10.1103\/PhysRevA.71.026702","journal-title":"Phys Rev A"},{"key":"3675_CR32","doi-asserted-by":"publisher","first-page":"403","DOI":"10.1016\/0021-9991(76)90041-3","volume":"22","author":"DT Gillespie","year":"1976","unstructured":"Gillespie DT: A general method for numerically simulating the stochastic time evolution of coupled chemical reactions. J Comput Phys 1976, 22: 403\u2013434. 10.1016\/0021-9991(76)90041-3","journal-title":"J Comput Phys"},{"key":"3675_CR33","doi-asserted-by":"publisher","first-page":"2340","DOI":"10.1021\/j100540a008","volume":"81","author":"DT Gillespie","year":"1977","unstructured":"Gillespie DT: Exact stochastic simulation of coupled chemical reactions. J Phys Chem 1977, 81: 2340\u20132361. 10.1021\/j100540a008","journal-title":"J Phys Chem"},{"key":"3675_CR34","doi-asserted-by":"publisher","first-page":"1876","DOI":"10.1021\/jp993732q","volume":"104","author":"MA Gibson","year":"2000","unstructured":"Gibson MA, Bruck J: Efficient Exact Stochastic Simulation of Chemical Systems with Many Species and Many Channels. J Phys Chem 2000, 104: 1876\u20131889.","journal-title":"J Phys Chem"},{"key":"3675_CR35","doi-asserted-by":"publisher","first-page":"253","DOI":"10.1007\/s10820-006-9042-9","volume":"14","author":"A Chatterjee","year":"2007","unstructured":"Chatterjee A, Vlachos DG: An overview of spatial microscopic and accelerated kinetic Monte Carlo methods. Journal of Computer-Aided Materials Design 2007, 14: 253\u2013308. 10.1007\/s10820-006-9042-9","journal-title":"Journal of Computer-Aided Materials Design"},{"key":"3675_CR36","doi-asserted-by":"publisher","first-page":"2266","DOI":"10.1529\/biophysj.104.054106","volume":"88","author":"K Ritchie","year":"2005","unstructured":"Ritchie K, Shan XY, Kondo J, Iwasawa K, Fujiwara T, Kusumi A: Detection of non-Brownian diffusion in the cell membrane in single molecule tracking. Biophys J 2005, 88: 2266\u20132277. 10.1529\/biophysj.104.054106","journal-title":"Biophys J"},{"key":"3675_CR37","doi-asserted-by":"publisher","first-page":"9412","DOI":"10.1063\/1.1616513","volume":"119","author":"MA Katsoulakis","year":"2003","unstructured":"Katsoulakis MA, Vlachos DG: Coarse-grained stochastic processes and kinetic Monte Carlo simulators for the diffusion of interacting particles. J Chem Phys 2003, 119: 9412\u20139427. 10.1063\/1.1616513","journal-title":"J Chem Phys"},{"key":"3675_CR38","doi-asserted-by":"publisher","first-page":"184101","DOI":"10.1063\/1.3005225","volume":"129","author":"SD Collins","year":"2008","unstructured":"Collins SD, Chatterjee A, Vlachos DG: Coarse-grained kinetic Monte Carlo models: Complex lattices, multicomponent systems, and homogenization at the stochastic level. J Chem Phys 2008, 129: 184101. 10.1063\/1.3005225","journal-title":"J Chem Phys"},{"key":"3675_CR39","doi-asserted-by":"publisher","first-page":"3111","DOI":"10.1073\/pnas.72.8.3111","volume":"72","author":"PG Saffman","year":"1975","unstructured":"Saffman PG, Delbr\u00fcck M: Brownian motion in biological membranes. Proc Nat Acad Sci USA 1975, 72: 3111\u20133113. 10.1073\/pnas.72.8.3111","journal-title":"Proc Nat Acad Sci USA"}],"container-title":["BMC Bioinformatics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/1471-2105-11-218.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,9,1]],"date-time":"2021-09-01T05:22:27Z","timestamp":1630473747000},"score":1,"resource":{"primary":{"URL":"https:\/\/bmcbioinformatics.biomedcentral.com\/articles\/10.1186\/1471-2105-11-218"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2010,4,29]]},"references-count":39,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2010,12]]}},"alternative-id":["3675"],"URL":"https:\/\/doi.org\/10.1186\/1471-2105-11-218","relation":{},"ISSN":["1471-2105"],"issn-type":[{"value":"1471-2105","type":"electronic"}],"subject":[],"published":{"date-parts":[[2010,4,29]]},"assertion":[{"value":"26 September 2009","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"29 April 2010","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"29 April 2010","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}}],"article-number":"218"}}