title: Structural analysis of in silico mutant experiments of human inner-kinetochore structure.
abstract: Large multi-molecular complexes like the kinetochore are lacking of suitable methods to determine their spatial structure. Here, we use and evaluate a novel modeling approach that combines rule-bases reaction network models with spatial molecular geometries. In particular, we introduce a method that allows to study in silico the influence of single interactions (e.g. bonds) on the spatial organization of large multi-molecular complexes and apply this method to an extended model of the human inner-kinetochore. Our computational analysis method encompasses determination of bond frequency, geometrical distances, statistical moments, and inter-dependencies between bonds using mutual information. For the analysis we have extend our previously reported human inner-kinetochore model by adding 13 new protein interactions and three protein geometry details. The model is validated by comparing the results of in silico with reported in vitro single protein deletion experiments. Our studies revealed that most simulations mimic the in vitro behavior of the kinetochore complex as expected. To identify the most important bonds in this model, we have created 39 mutants in silico by selectively disabling single protein interactions. In a total of 11,800 simulation runs we have compared the resulting structures to the wild-type. In particular, this allowed us to identify the interaction Cenp-W-H3 and Cenp-S-Cenp-X as having the strongest influence on the inner-kinetochore's structure. We conclude that our approach can become a useful tool for the in silico dynamical study of large, multi-molecular complexes.
authors.affiliation: Bio Systems Analysis Group, Institute of Computer Science, Jena Centre for Bioinformatics and Friedrich Schiller University Jena, 07743 Jena, Germany. Electronic address: richard.henze@uni-jena.de.
authors.forename: Richard
authors.initials: R
authors.lastname: Henze
authors.affiliation: Bio Systems Analysis Group, Institute of Computer Science, Jena Centre for Bioinformatics and Friedrich Schiller University Jena, 07743 Jena, Germany. Electronic address: ja.hu.03@uni-jena.de.
authors.forename: Jan
authors.initials: J
authors.lastname: Huwald
authors.affiliation: Bio Systems Analysis Group, Institute of Computer Science, Jena Centre for Bioinformatics and Friedrich Schiller University Jena, 07743 Jena, Germany. Electronic address: nelly.mostajo@upch.pe.
authors.forename: Nelly
authors.initials: N
authors.lastname: Mostajo
authors.affiliation: Bio Systems Analysis Group, Institute of Computer Science, Jena Centre for Bioinformatics and Friedrich Schiller University Jena, 07743 Jena, Germany. Electronic address: peter.dittrich@uni-jena.de.
authors.forename: Peter
authors.initials: P
authors.lastname: Dittrich
authors.affiliation: Bio Systems Analysis Group, Institute of Computer Science, Jena Centre for Bioinformatics and Friedrich Schiller University Jena, 07743 Jena, Germany; Umm Al-Qura University, 1109 Makkah Al-Mukarramah, Saudi Arabia; Al-Qunfudah Center for Scientific Research (QCSR), 21912 Al-Qunfudah, Saudi Arabia. Electronic address: bashar.ibrahim@uni-jena.de.
authors.forename: Bashar
authors.initials: B
authors.lastname: Ibrahim
mesh_terms: D003198:Computer Simulation; D006801:Humans; D018386:Kinetochores / Q000737:chemistry*; D008958:Models, Molecular; D011485:Protein Binding; D011487:Protein Conformation; D025941:Protein Interaction Mapping
keywords: Bond mutation; Inner-kinetochore structure; Modeling; Rule-based; Simulation; Structural analysis