title: Spatiotemporal multistage consensus clustering in molecular dynamics studies of large proteins.
abstract: The aim of this work is to find semi-rigid domains within large proteins as reference structures for fitting molecular dynamics trajectories. We propose an algorithm, multistage consensus clustering, MCC, based on minimum variation of distances between pairs of Cα-atoms as target function. The whole dataset (trajectory) is split into sub-segments. For a given sub-segment, spatial clustering is repeatedly started from different random seeds, and we adopt the specific spatial clustering with minimum target function: the process described so far is stage 1 of MCC. Then, in stage 2, the results of spatial clustering are consolidated, to arrive at domains stable over the whole dataset. We found that MCC is robust regarding the choice of parameters and yields relevant information on functional domains of the major histocompatibility complex (MHC) studied in this paper: the α-helices and β-floor of the protein (MHC) proved to be most flexible and did not contribute to clusters of significant size. Three alleles of the MHC, each in complex with ABCD3 peptide and LC13 T-cell receptor (TCR), yielded different patterns of motion. Those alleles causing immunological allo-reactions showed distinct correlations of motion between parts of the peptide, the binding cleft and the complementary determining regions (CDR)-loops of the TCR. Multistage consensus clustering reflected functional differences between MHC alleles and yields a methodological basis to increase sensitivity of functional analyses of bio-molecules. Due to the generality of approach, MCC is prone to lend itself as a potent tool also for the analysis of other kinds of big data.
authors.affiliation: Section of Biosimulation and Bioinformatics, Center for Medical Statistics, Informatics and Intelligent Systems (CeMSIIS), Medical University of Vienna, Spitalgasse 23, A-1090 Vienna, Austria. wolfgang.schreiner@meduniwien.ac.at.
authors.forename: Michael
authors.initials: M
authors.lastname: Kenn
authors.affiliation: Section of Biosimulation and Bioinformatics, Center for Medical Statistics, Informatics and Intelligent Systems (CeMSIIS), Medical University of Vienna, Spitalgasse 23, A-1090 Vienna, Austria. wolfgang.schreiner@meduniwien.ac.at.
authors.forename: Reiner
authors.initials: R
authors.lastname: Ribarics
authors.affiliation: Institute of Information and Communication Technologies (IICT), Bulgarian Academy of Sciences, 25A, Acad. G. Bonchev Str., Sofia 1113, Bulgaria.
authors.forename: Nevena
authors.initials: N
authors.lastname: Ilieva
authors.affiliation: Section of Biosimulation and Bioinformatics, Center for Medical Statistics, Informatics and Intelligent Systems (CeMSIIS), Medical University of Vienna, Spitalgasse 23, A-1090 Vienna, Austria. wolfgang.schreiner@meduniwien.ac.at.
authors.forename: Michael
authors.initials: M
authors.lastname: Cibena
authors.affiliation: Section of Biosimulation and Bioinformatics, Center for Medical Statistics, Informatics and Intelligent Systems (CeMSIIS), Medical University of Vienna, Spitalgasse 23, A-1090 Vienna, Austria. wolfgang.schreiner@meduniwien.ac.at.
authors.forename: Rudolf
authors.initials: R
authors.lastname: Karch
authors.affiliation: Section of Biosimulation and Bioinformatics, Center for Medical Statistics, Informatics and Intelligent Systems (CeMSIIS), Medical University of Vienna, Spitalgasse 23, A-1090 Vienna, Austria. wolfgang.schreiner@meduniwien.ac.at.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Schreiner
mesh_terms: D000465:Algorithms; D016827:CD8 Antigens / Q000737:chemistry / Q000378:metabolism; D016000:Cluster Analysis; D008285:Major Histocompatibility Complex; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D046912:Multiprotein Complexes / Q000737:chemistry; D011487:Protein Conformation; D054730:Protein Interaction Domains and Motifs; D011506:Proteins / Q000737:chemistry* / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000737:chemistry / Q000378:metabolism
chemical_list: D016827:CD8 Antigens; D046912:Multiprotein Complexes; D011506:Proteins; D011948:Receptors, Antigen, T-Cell