{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,12]],"date-time":"2026-03-12T00:10:30Z","timestamp":1773274230362,"version":"3.50.1"},"reference-count":37,"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":[[2008,12]]},"abstract":"<jats:title>Abstract<\/jats:title>\n          <jats:sec>\n            <jats:title>Background<\/jats:title>\n            <jats:p>Recent approaches for predicting the three-dimensional (3D) structure of proteins such as <jats:italic>de novo<\/jats:italic> or fold recognition methods mostly rely on simplified energy potential functions and a reduced representation of the polypeptide chain. These simplifications facilitate the exploration of the protein conformational space but do not permit to capture entirely the subtle relationship that exists between the amino acid sequence and its native structure. It has been proposed that physics-based energy functions together with techniques for sampling the conformational space, e.g., Monte Carlo or molecular dynamics (MD) simulations, are better suited to the task of modelling proteins at higher resolutions than those of models obtained with the former type of methods. In this study we monitor different protein structural properties along MD trajectories to discriminate correct from erroneous models. These models are based on the sequence-structure alignments provided by our fold recognition method, FROST. We define correct models as being built from alignments of sequences with structures similar to their native structures and erroneous models from alignments of sequences with structures unrelated to their native structures.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Results<\/jats:title>\n            <jats:p>For three test sequences whose native structures belong to the all-<jats:italic>\u03b1<\/jats:italic>, all-<jats:italic>\u03b2<\/jats:italic> and <jats:italic>\u03b1\u03b2<\/jats:italic> classes we built a set of models intended to cover the whole spectrum: from a perfect model, i.e., the native structure, to a very poor model, i.e., a random alignment of the test sequence with a structure belonging to another structural class, including several intermediate models based on fold recognition alignments. We submitted these models to 11 ns of MD simulations at three different temperatures. We monitored along the corresponding trajectories the mean of the Root-Mean-Square deviations (RMSd) with respect to the initial conformation, the RMSd fluctuations, the number of conformation clusters, the evolution of secondary structures and the surface area of residues. None of these criteria alone is 100% efficient in discriminating correct from erroneous models. The mean RMSd, RMSd fluctuations, secondary structure and clustering of conformations show some false positives whereas the residue surface area criterion shows false negatives. However if we consider these criteria in combination it is straightforward to discriminate the two types of models.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusion<\/jats:title>\n            <jats:p>The ability of discriminating correct from erroneous models allows us to improve the specificity and sensitivity of our fold recognition method for a number of ambiguous cases.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1186\/1471-2105-9-6","type":"journal-article","created":{"date-parts":[[2008,2,15]],"date-time":"2008-02-15T19:13:39Z","timestamp":1203102819000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Can molecular dynamics simulations help in discriminating correct from erroneous protein 3D models?"],"prefix":"10.1186","volume":"9","author":[{"given":"Jean-Fran\u00e7ois","family":"Taly","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Antoine","family":"Marin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jean-Fran\u00e7ois","family":"Gibrat","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2008,1,7]]},"reference":[{"issue":"Suppl 7","key":"1991_CR1","doi-asserted-by":"publisher","first-page":"225","DOI":"10.1002\/prot.20740","volume":"61","author":"A Kryshtafovych","year":"2005","unstructured":"Kryshtafovych A, Venclovas C, Fidelis K, Moult J: Progress over the first decade of CASP experiments. Proteins 2005, 61(Suppl 7):225\u201336. 10.1002\/prot.20740","journal-title":"Proteins"},{"key":"1991_CR2","doi-asserted-by":"publisher","first-page":"7547","DOI":"10.1073\/pnas.0502655102","volume":"102","author":"S Oldziej","year":"2005","unstructured":"Oldziej S, Czaplewski C, Liwo A, Chinchio M, Nanias M, Vila JA, Khalili M, Arnautova YA, Jagielska A, Makowski M, Schafroth HD, Kazmierkiewicz R, Ripoll DR, Pillardy J, Saunders JA, Kang YK, Gibson KD, Scheraga HA: Physics-based protein-structure prediction using a hierarchical protocol based on the UNRES force field: assessment in two blind tests. Proc Natl Acad Sci USA 2005, 102: 7547\u201352. 10.1073\/pnas.0502655102","journal-title":"Proc Natl Acad Sci USA"},{"key":"1991_CR3","doi-asserted-by":"publisher","first-page":"638","DOI":"10.1126\/science.1112160","volume":"310","author":"O Schueler-Furman","year":"2005","unstructured":"Schueler-Furman O, Wang C, Bradley P, Misura K, Baker D: Progress in modeling of protein structures and interactions. Science 2005, 310: 638\u201342. 10.1126\/science.1112160","journal-title":"Science"},{"key":"1991_CR4","doi-asserted-by":"publisher","first-page":"139","DOI":"10.1016\/S0959-440X(00)00063-4","volume":"10","author":"T Lazaridis","year":"2000","unstructured":"Lazaridis T, Karplus M: Effective energy functions for protein structure prediction. Curr Opin Struct Biol 2000, 10: 139\u201345. 10.1016\/S0959-440X(00)00063-4","journal-title":"Curr Opin Struct Biol"},{"key":"1991_CR5","doi-asserted-by":"publisher","first-page":"787","DOI":"10.1016\/0022-2836(84)90049-4","volume":"177","author":"J Novotny","year":"1984","unstructured":"Novotny J, Bruccoleri R, Karplus M: An analysis of incorrectly folded protein models. Implications for structure predictions. J Mol Biol 1984, 177: 787\u2013818. 10.1016\/0022-2836(84)90049-4","journal-title":"J Mol Biol"},{"key":"1991_CR6","doi-asserted-by":"publisher","first-page":"19","DOI":"10.1002\/prot.340040105","volume":"4","author":"J Novotny","year":"1988","unstructured":"Novotny J, Rashin AA, Bruccoleri RE: Criteria that discriminate between native proteins and incorrectly folded models. Proteins 1988, 4: 19\u201330. 10.1002\/prot.340040105","journal-title":"Proteins"},{"key":"1991_CR7","doi-asserted-by":"publisher","first-page":"399","DOI":"10.1002\/(SICI)1097-0134(19980901)32:4<399::AID-PROT1>3.0.CO;2-C","volume":"32","author":"YN Vorobjev","year":"1998","unstructured":"Vorobjev YN, Almagro JC, Hermans J: Discrimination between native and intentionally misfolded conformations of proteins: ES\/IS, a new method for calculating conformational free energy that uses both dynamics simulations with an explicit solvent and an implicit solvent continuum model. Proteins 1998, 32: 399\u2013413. 10.1002\/(SICI)1097-0134(19980901)32:4<399::AID-PROT1>3.0.CO;2-C","journal-title":"Proteins"},{"key":"1991_CR8","doi-asserted-by":"publisher","first-page":"1772","DOI":"10.1002\/pro.5560070812","volume":"7","author":"A Janardhan","year":"1998","unstructured":"Janardhan A, Vajda S: Selecting near-native conformations in homology modeling: the role of molecular mechanics and solvation terms. Protein Sci 1998, 7: 1772\u201380.","journal-title":"Protein Sci"},{"key":"1991_CR9","doi-asserted-by":"publisher","first-page":"477","DOI":"10.1006\/jmbi.1999.2685","volume":"288","author":"T Lazaridis","year":"1999","unstructured":"Lazaridis T, Karplus M: Discrimination of the native from misfolded protein models with an energy function including implicit solvation. J Mol Biol 1999, 288: 477\u201387. 10.1006\/jmbi.1999.2685","journal-title":"J Mol Biol"},{"key":"1991_CR10","doi-asserted-by":"publisher","first-page":"518","DOI":"10.1002\/1097-0134(20001201)41:4<518::AID-PROT90>3.0.CO;2-6","volume":"41","author":"DW Gatchell","year":"2000","unstructured":"Gatchell DW, Dennis S, Vajda S: Discrimination of near-native protein structures from misfolded models by empirical free energy functions. Proteins 2000, 41: 518\u201334. 10.1002\/1097-0134(20001201)41:4<518::AID-PROT90>3.0.CO;2-6","journal-title":"Proteins"},{"key":"1991_CR11","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1007\/s002490000111","volume":"30","author":"AR Kinjo","year":"2001","unstructured":"Kinjo AR, Kidera A, Nakamura H, Nishikawa K: Physicochemical evaluation of protein folds predicted by threading. Eur Biophys J 2001, 30: 1\u201310. 10.1007\/s002490000111","journal-title":"Eur Biophys J"},{"key":"1991_CR12","doi-asserted-by":"publisher","first-page":"147","DOI":"10.1002\/jcc.10018","volume":"23","author":"BN Dominy","year":"2002","unstructured":"Dominy BN, Brooks CL III: Identifying native-like protein structures using physics-based potentials. J Comput Chem 2002, 23: 147\u201360. 10.1002\/jcc.10018","journal-title":"J Comput Chem"},{"key":"1991_CR13","doi-asserted-by":"publisher","first-page":"404","DOI":"10.1002\/prot.10171","volume":"48","author":"AK Felts","year":"2002","unstructured":"Felts AK, Gallicchio E, Wallqvist A, Levy RM: Distinguishing native conformations of proteins from decoys with an effective free energy estimator based on the OPLS all-atom force field and the Surface Generalized Born solvent model. Proteins 2002, 48: 404\u201322. 10.1002\/prot.10171","journal-title":"Proteins"},{"key":"1991_CR14","doi-asserted-by":"publisher","first-page":"417","DOI":"10.1006\/jmbi.2001.5032","volume":"313","author":"MR Lee","year":"2001","unstructured":"Lee MR, Tsai J, Baker D, Kollman PA: Molecular dynamics in the endgame of protein structure prediction. J Mol Biol 2001, 313: 417\u201330. 10.1006\/jmbi.2001.5032","journal-title":"J Mol Biol"},{"key":"1991_CR15","doi-asserted-by":"publisher","first-page":"211","DOI":"10.1110\/ps.03381404","volume":"13","author":"H Fan","year":"2004","unstructured":"Fan H, Mark AE: Refinement of homology-based protein structures by molecular dynamics simulation techniques. Protein Sci 2004, 13: 211\u201320. 10.1110\/ps.03381404","journal-title":"Protein Sci"},{"issue":"4","key":"1991_CR16","doi-asserted-by":"publisher","first-page":"922","DOI":"10.1002\/prot.21345","volume":"67","author":"J Chen","year":"2007","unstructured":"Chen J, Brooks CL 3rd: Can molecular dynamics simulations provide high-resolution refinement of protein structure? Proteins 2007, 67(4):922\u2013930. 10.1002\/prot.21345","journal-title":"Proteins"},{"key":"1991_CR17","doi-asserted-by":"publisher","first-page":"493","DOI":"10.1002\/prot.10231","volume":"49","author":"A Marin","year":"2002","unstructured":"Marin A, Pothier J, Zimmermann K, Gibrat JF: FROST: a filter-based fold recognition method. Proteins 2002, 49: 493\u2013509. 10.1002\/prot.10231","journal-title":"Proteins"},{"key":"1991_CR18","doi-asserted-by":"publisher","first-page":"D226","DOI":"10.1093\/nar\/gkh039","volume":"32","author":"A Andreeva","year":"2004","unstructured":"Andreeva A, Howorth D, Brenner SE, Hubbard TJ, Chothia C, Murzin AG: SCOP database in 2004: refinements integrate structure and sequence family data. Nucleic Acids Res 2004, 32: D226\u20139. 10.1093\/nar\/gkh039","journal-title":"Nucleic Acids Res"},{"key":"1991_CR19","doi-asserted-by":"publisher","first-page":"430","DOI":"10.1002\/pro.110430","volume":"11","author":"F Melo","year":"2002","unstructured":"Melo F, Sanchez R, Sali A: Statistical potentials for fold assessment. Protein Sci 2002, 11: 430\u201348. 10.1110\/ps.25502","journal-title":"Protein Sci"},{"key":"1991_CR20","doi-asserted-by":"publisher","first-page":"8438","DOI":"10.1103\/PhysRevE.62.8438","volume":"62","author":"B Hess","year":"2000","unstructured":"Hess B: Similarities between principal components of protein dynamics and random diffusion. Phys Rev E 2000, 62: 8438\u201348. 10.1103\/PhysRevE.62.8438","journal-title":"Phys Rev E"},{"key":"1991_CR21","doi-asserted-by":"publisher","first-page":"031910,1","DOI":"10.1103\/PhysRevE.65.031910","volume":"65","author":"B Hess","year":"2002","unstructured":"Hess B: Convergence of sampling in protein simulations. Phys Rev E 2002, 65: 031910,1\u2013031910,10. 10.1103\/PhysRevE.65.031910","journal-title":"Phys Rev E"},{"issue":"12","key":"1991_CR22","doi-asserted-by":"publisher","first-page":"2577","DOI":"10.1002\/bip.360221211","volume":"22","author":"W Kabsch","year":"1983","unstructured":"Kabsch W, Sander C: Dictionary of protein secondary structure: pattern recognition of hydrogen-bonded and geometrical features. Biopolymers 1983, 22(12):2577\u2013637. 10.1002\/bip.360221211","journal-title":"Biopolymers"},{"key":"1991_CR23","doi-asserted-by":"publisher","first-page":"58","DOI":"10.1002\/1097-0134(20001001)41:1<58::AID-PROT90>3.0.CO;2-3","volume":"41","author":"B Gilquin","year":"2000","unstructured":"Gilquin B, Guilbert C, Perahia D: Unfolding of hen egg lysozyme by molecular dynamics simulations at 300 K: insight into the role of the interdomain interface. Proteins 2000, 41: 58\u201374. 10.1002\/1097-0134(20001001)41:1<58::AID-PROT90>3.0.CO;2-3","journal-title":"Proteins"},{"key":"1991_CR24","doi-asserted-by":"publisher","first-page":"1868","DOI":"10.1126\/science.1113801","volume":"309","author":"P Bradley","year":"2005","unstructured":"Bradley P, Misura KM, Baker D: Toward high-resolution de novo structure prediction for small proteins. Science 2005, 309: 1868\u201371. 10.1126\/science.1113801","journal-title":"Science"},{"key":"1991_CR25","doi-asserted-by":"publisher","first-page":"43","DOI":"10.1186\/1472-6807-7-43","volume":"7","author":"S Kmiecik","year":"2007","unstructured":"Kmiecik S, Gront D, Kolinski A: Towards the high-resolution protein structure prediction. Fast refinement of reduced models with all-atom force field. BMC Struct Biol 2007, 7: 43. 10.1186\/1472-6807-7-43","journal-title":"BMC Struct Biol"},{"key":"1991_CR26","doi-asserted-by":"publisher","first-page":"8392","DOI":"10.1021\/ja993119k","volume":"122","author":"C Simmerling","year":"2000","unstructured":"Simmerling C, Lee MR, Ortiz AR, Kolinski A, Skolnick J, Kollman PA: Combining MONSSTER and LES\/PME to predict protein structure from amino acid sequence: application to the small protein CMTI-1. J Am Chem Soc 2000, 122: 8392\u20138402. 10.1021\/ja993119k","journal-title":"J Am Chem Soc"},{"key":"1991_CR27","doi-asserted-by":"publisher","first-page":"3533","DOI":"10.1093\/nar\/gkl471","volume":"34","author":"K Bryson","year":"2006","unstructured":"Bryson K, Loux V, Bossy R, Nicolas P, Chaillou S, van de Guchte M, Penaud S, Maguin E, Hoebeke M, Bessieres P, Gibrat JF: AGMIAL: implementing an annotation strategy for prokaryote genomes as a distributed system. Nucleic Acids Res 2006, 34: 3533\u201345. 10.1093\/nar\/gkl471","journal-title":"Nucleic Acids Res"},{"key":"1991_CR28","doi-asserted-by":"publisher","first-page":"260","DOI":"10.1093\/nar\/30.1.260","volume":"30","author":"JM Chandonia","year":"2002","unstructured":"Chandonia JM, Walker NS, Lo Conte L, Koehl P, Levitt M, Brenner SE: ASTRAL compendium enhancements. Nucleic Acids Res 2002, 30: 260\u20133. 10.1093\/nar\/30.1.260","journal-title":"Nucleic Acids Res"},{"key":"1991_CR29","doi-asserted-by":"publisher","first-page":"356","DOI":"10.1002\/prot.340230309","volume":"23","author":"T Madej","year":"1995","unstructured":"Madej T, Gibrat JF, Bryant SH: Threading a database of protein cores. Proteins 1995, 23: 356\u201369. 10.1002\/prot.340230309","journal-title":"Proteins"},{"key":"1991_CR30","doi-asserted-by":"publisher","first-page":"377","DOI":"10.1016\/S0959-440X(96)80058-3","volume":"6","author":"JF Gibrat","year":"1996","unstructured":"Gibrat JF, Madej T, Bryant SH: Surprising similarities in structure comparison. Curr Opin Struct Biol 1996, 6: 377\u201385. 10.1016\/S0959-440X(96)80058-3","journal-title":"Curr Opin Struct Biol"},{"key":"1991_CR31","doi-asserted-by":"publisher","first-page":"702","DOI":"10.1002\/prot.20264","volume":"57","author":"Y Zhang","year":"2004","unstructured":"Zhang Y, Skolnick J: Scoring function for automated assessment of protein structure template quality. Proteins 2004, 57: 702\u201310. 10.1002\/prot.20264","journal-title":"Proteins"},{"key":"1991_CR32","doi-asserted-by":"publisher","first-page":"779","DOI":"10.1006\/jmbi.1993.1626","volume":"234","author":"A Sali","year":"1993","unstructured":"Sali A, Blundell TL: Comparative protein modelling by satisfaction of spatial restraints. J Mol Biol 1993, 234: 779\u2013815. 10.1006\/jmbi.1993.1626","journal-title":"J Mol Biol"},{"key":"1991_CR33","doi-asserted-by":"publisher","first-page":"1701","DOI":"10.1002\/jcc.20291","volume":"26","author":"D Van Der Spoel","year":"2005","unstructured":"Van Der Spoel D, Lindahl E, Hess B, Groenhof G, Mark AE, Berendsen HJ: GROMACS: fast, flexible, and free. J Comput Chem 2005, 26: 1701\u201318. 10.1002\/jcc.20291","journal-title":"J Comput Chem"},{"key":"1991_CR34","doi-asserted-by":"publisher","first-page":"649","DOI":"10.1002\/pro.5560070314","volume":"7","author":"L Caves","year":"1998","unstructured":"Caves L, Evanseck J, Karplus M: Locally accessible conformations of proteins: multiple molecular dynamics simulations of crambin. Protein Sci 1998, 7: 649\u201366.","journal-title":"Protein Sci"},{"key":"1991_CR35","volume-title":"Statistical Mechanics","author":"DA McQuarrie","year":"1976","unstructured":"McQuarrie DA: Statistical Mechanics. New-York: HarperCollins; 1976."},{"key":"1991_CR36","doi-asserted-by":"publisher","first-page":"396","DOI":"10.1016\/S0076-6879(97)77022-8","volume":"277","author":"D Eisenberg","year":"1997","unstructured":"Eisenberg D, Luthy R, Bowie JU: VERIFY3D: assessment of protein models with three-dimensional profiles. Methods Enzymol 1997, 277: 396\u2013404.","journal-title":"Methods Enzymol"},{"key":"1991_CR37","doi-asserted-by":"publisher","first-page":"33","DOI":"10.1016\/0263-7855(96)00018-5","volume":"14","author":"W Humphrey","year":"1996","unstructured":"Humphrey W, Dalke A, Schulten K: VMD \u2013 Visual Molecular Dynamics. J Molec Graphics 1996, 14: 33\u201338. 10.1016\/0263-7855(96)00018-5","journal-title":"J Molec Graphics"}],"container-title":["BMC Bioinformatics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/1471-2105-9-6.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,9,1]],"date-time":"2021-09-01T03:23:54Z","timestamp":1630466634000},"score":1,"resource":{"primary":{"URL":"https:\/\/bmcbioinformatics.biomedcentral.com\/articles\/10.1186\/1471-2105-9-6"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2008,1,7]]},"references-count":37,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2008,12]]}},"alternative-id":["1991"],"URL":"https:\/\/doi.org\/10.1186\/1471-2105-9-6","relation":{},"ISSN":["1471-2105"],"issn-type":[{"value":"1471-2105","type":"electronic"}],"subject":[],"published":{"date-parts":[[2008,1,7]]},"assertion":[{"value":"18 July 2007","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"7 January 2008","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"7 January 2008","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}}],"article-number":"6"}}