Heidelberg Institute for Theoretical Studies HITS gGmbH

Heidelberg, Germany

Heidelberg Institute for Theoretical Studies HITS gGmbH

Heidelberg, Germany
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Wittig U.,Heidelberg Institute for Theoretical Studies HITS gGmbH | Rey M.,Heidelberg Institute for Theoretical Studies HITS gGmbH | Weidemann A.,Heidelberg Institute for Theoretical Studies HITS gGmbH | Muller W.,Heidelberg Institute for Theoretical Studies HITS gGmbH
Journal of Biotechnology | Year: 2017

Collecting, curating, interlinking, and sharing high quality data are central to de.NBI-SysBio, the systems biology data management service center within the de.NBI network (German Network for Bioinformatics Infrastructure). The work of the center is guided by the FAIR principles for scientific data management and stewardship. FAIR stands for the four foundational principles Findability, Accessibility, Interoperability, and Reusability which were established to enhance the ability of machines to automatically find, access, exchange and use data.Within this overview paper we describe three tools (SABIO-RK, Excemplify, SEEK) that exemplify the contribution of de.NBI-SysBio services to FAIR data, models, and experimental methods storage and exchange. The interconnectivity of the tools and the data workflow within systems biology projects will be explained. For many years we are the German partner in the FAIRDOM initiative (http://fair-dom.org) to establish a European data and model management service facility for systems biology. © 2017 The Authors.

Kokh D.B.,Heidelberg Institute for Theoretical Studies HITS gGmbH | Wade R.C.,Heidelberg Institute for Theoretical Studies HITS gGmbH | Wenzel W.,Karlsruhe Institute of Technology
Wiley Interdisciplinary Reviews: Computational Molecular Science | Year: 2011

Protein structural flexibility plays a critical role in receptor-ligand binding processes and should be considered in computational drug design. However, the treatment of protein conformational changes is still a major challenge because it is associated with a large increase in the conformational space that needs to be sampled and requires highly accurate scoring functions that incorporate the receptor reorganization energy. A number of different approaches have been proposed recently to address this problem. Most of them have been shown to be successful in reproducing the correct docking pose of known ligands, but their benefit regarding enrichment, affinity prediction, and screening of large molecular libraries is less clear. Here, we review current methodologies to treat receptor conformational changes in structure-based docking procedures, and show their impact on the accuracy of docking and scoring. We also discuss pitfalls and limitations of state-of-the-art flexible-receptor docking strategies and perspectives for their improvement. © 2011 John Wiley & Sons, Ltd.

Mereghetti P.,Heidelberg Institute for Theoretical Studies HITS GGmbH | Mereghetti P.,The Interdisciplinary Center | Wade R.C.,Heidelberg Institute for Theoretical Studies HITS GGmbH | Wade R.C.,University of Heidelberg
Journal of Physical Chemistry B | Year: 2012

High macromolecular concentrations are a distinguishing feature of living organisms. Understanding how the high concentration of solutes affects the dynamic properties of biological macromolecules is fundamental for the comprehension of biological processes in living systems. In this paper, we describe the implementation of mean field models of translational and rotational hydrodynamic interactions into an atomically detailed many-protein Brownian dynamics simulation method. Concentrated solutions (30-40% volume fraction) of myoglobin, hemoglobin A, and sickle cell hemoglobin S were simulated, and static structure factors, oligomer formation, and translational and rotational self-diffusion coefficients were computed. Good agreement of computed properties with available experimental data was obtained. The results show the importance of both solvent mediated interactions and weak protein-protein interactions for accurately describing the dynamics and the association properties of concentrated protein solutions. Specifically, they show a qualitative difference in the translational and rotational dynamics of the systems studied. Although the translational diffusion coefficient is controlled by macromolecular shape and hydrodynamic interactions, the rotational diffusion coefficient is affected by macromolecular shape, direct intermolecular interactions, and both translational and rotational hydrodynamic interactions. © 2012 American Chemical Society.

Pachov G.V.,Heidelberg Institute for Theoretical Studies HITS GGmbH | Gabdoulline R.R.,Heidelberg Institute for Theoretical Studies HITS GGmbH | Gabdoulline R.R.,University of Heidelberg | Gabdoulline R.R.,BIOBASE GmbH | Wade R.C.,Heidelberg Institute for Theoretical Studies HITS GGmbH
Nucleic Acids Research | Year: 2011

Several different models of the linker histone (LH)-nucleosome complex have been proposed, but none of them has unambiguously revealed the position and binding sites of the LH on the nucleosome. Using Brownian dynamics-based docking together with normal mode analysis of the nucleosome to account for the flexibility of two flanking 10bp long linker DNAs (L-DNA), we identified binding modes of the H5-LH globular domain (GH5) to the nucleosome. For a wide range of nucleosomal conformations with the L-DNA ends less than 65 apart, one dominant binding mode was identified for GH5 and found to be consistent with fluorescence recovery after photobleaching (FRAP) experiments. GH5 binds asymmetrically with respect to the nucleosomal dyad axis, fitting between the nucleosomal DNA and one of the L-DNAs. For greater distances between L-DNA ends, docking of GH5 to the L-DNA that is more restrained and less open becomes favored. These results suggest a selection mechanism by which GH5 preferentially binds one of the L-DNAs and thereby affects DNA dynamics and accessibility and contributes to formation of a particular chromatin fiber structure. The two binding modes identified would, respectively, favor a tight zigzag chromatin structure or a loose solenoid chromatin fiber. © 2011 The Author(s).

Kokh D.B.,Heidelberg Institute for Theoretical Studies HITS GGmbH | Corni S.,National Research Council Italy | Winn P.J.,University of Birmingham | Hoefling M.,Ludwig Maximilians University of Munich | And 2 more authors.
Journal of Chemical Theory and Computation | Year: 2010

In order to study protein-inorganic surface association processes, we have developed a physics-based energy model, the ProMetCS model, which describes protein-surface interactions at the atomistic level while treating the solvent as a continuum. Here, we present an approach to modeling the interaction of a protein with an atomically flat Au(111) surface in an aqueous solvent. Protein-gold interactions are modeled as the sum of van der Waals, weak chemisorption, and electrostatic interactions, as well as the change in free energy due to partial desolvation of the protein and the metal surface upon association. This desolvation energy includes the effects of water-protein, water-surface, and water-water interactions and has been parametrized using molecular dynamics (MD) simulations of water molecules and a test atom at a gold-water interface. The proposed procedure for computing the energy terms is mostly grid-based and is therefore efficient for application to long-time simulations of protein binding processes. The approach was tested for capped amino acid residues whose potentials of mean force for binding to a gold surface were computed and compared with those obtained previously in MD simulations with water treated explicitly. Calculations show good quantitative agreement with the results from MD simulations for all but one amino acid (Trp), as well as correspondence with available experimental data on the adhesion properties of amino acids. © 2010 American Chemical Society.

Wittig U.,Heidelberg Institute for Theoretical Studies HITS GGmbH | Kania R.,Heidelberg Institute for Theoretical Studies HITS GGmbH | Golebiewski M.,Heidelberg Institute for Theoretical Studies HITS GGmbH | Rey M.,Heidelberg Institute for Theoretical Studies HITS GGmbH | And 11 more authors.
Nucleic Acids Research | Year: 2012

SABIO-RK (http://sabio.h-its.org/) is a web-accessible database storing comprehensive information about biochemical reactions and their kinetic properties. SABIO-RK offers standardized data manually extracted from the literature and data directly submitted from lab experiments. The database content includes kinetic parameters in relation to biochemical reactions and their biological sources with no restriction on any particular set of organisms. Additionally, kinetic rate laws and corresponding equations as well as experimental conditions are represented. All the data are manually curated and annotated by biological experts, supported by automated consistency checks. SABIO-RK can be accessed via web-based user interfaces or automatically via web services that allow direct data access by other tools. Both interfaces support the export of the data together with its annotations in SBML (Systems Biology Markup Language), e.g. for import in modelling tools. © The Author(s) 2011.

Uddin R.,University of Karachi | Lodhi M.U.,University of Karachi | Ul-Haq Z.,University of Karachi | Ul-Haq Z.,Heidelberg Institute for Theoretical Studies HITS gGmbH
Chemical Biology and Drug Design | Year: 2012

Methicillin resistant Staphylococcus aureus has become a major health concern and it requires new therapeutic agents. Staphylococcus aureus Sortase A enzyme contributes in adherence of bacteria with the cell wall of host cell; consequently, inhibition of S. aureus Sortase A by small molecules could be employed as potential antibacterial agents against methicillin resistant S. aureus. Current study focused on the identification of 3D pharmacophoric features within a series of rhodanine, pyridazinone, and pyrazolethione analogs as S. aureus Sortase A inhibitors. Pharmacophore model was constructed employing representative molecules using Genetic Algorithm with Linear Assignment of Hypermolecular Alignment of Database. The identified pharmacophoric points were then utilized to create alignment hypothesis for three-dimensional quantitative structure-activity relationships. Outcome of comparative molecular field analysis and comparative molecular similarity indices analysis experiments were in good agreement (comparative molecular field analysis: q 2=0.562 and r 2=0.995, comparative molecular similarity indices analysis: q 2=0.549 and r 2=0.978) and capable of explaining the variance in biological activities coherently with respect to the structural features of compounds. The results were also found in concurrence with the outcome of pharmacophoric features. © 2012 John Wiley & Sons A/S.

Stamatakis A.,Heidelberg Institute for Theoretical Studies HITS gGmbH | Izquierdo-Carrasco F.,Heidelberg Institute for Theoretical Studies HITS gGmbH | Izquierdo-Carrasco F.,Exelixis
Briefings in Bioinformatics | Year: 2011

Verification in phylogenetics represents an extremely difficult subject. Phylogenetic analysis deals with the reconstruction of evolutionary histories of species, and as long as mankind is not able to travel in time, it will not be possible to verify deep evolutionary histories reconstructed with modern computational methods. Here, we focus on two more tangible issues that are related to verification in phylogenetics (i) the inference of support values on trees that provide some notion about the 'correctness' of the tree within narrow limits and, more importantly; (ii) issues pertaining to program verification, especially with respect to codes that rely heavily on floating-point arithmetics. Program verification represents a largely underestimated problem in computational science that can have fatal effects on scientific conclusions. © The Author 2011. Published by Oxford University Press.

Mereghetti P.,Heidelberg Institute for Theoretical Studies HITS gGmbH | Mereghetti P.,The Interdisciplinary Center | Wade R.C.,Heidelberg Institute for Theoretical Studies HITS gGmbH
BMC Biophysics | Year: 2011

Hydrophobins are small proteins produced by filamentous fungi that have a variety of biological functions including coating of spores and surface adhesion. To accomplish these functions, they rely on unique interface-binding properties. Using atomic-detail implicit solvent rigid-body Brownian dynamics simulations, we studied the diffusion of HFBI, a class II hydrophobin from Trichoderma reesei, in aqueous solution in the presence and absence of a graphite surface.Results: In the simulations, HFBI exists in solution as a mixture of monomers in equilibrium with different types of oligomers. The oligomerization state depends on the conformation of HFBI. When a Highly Ordered Pyrolytic Graphite (HOPG) layer is present in the simulated system, HFBI tends to interact with the HOPG layer through a hydrophobic patch on the protein.Conclusions: From the simulations of HFBI solutions, we identify a tetrameric encounter complex stabilized by non-polar interactions between the aliphatic residues in the hydrophobic patch on HFBI. After the formation of the encounter complex, a local structural rearrangement at the protein interfaces is required to obtain the tetrameric arrangement seen in HFBI crystals. Simulations performed with the graphite surface show that, due to a combination of a geometric hindrance and the interaction of the aliphatic sidechains with the graphite layer, HFBI proteins tend to accumulate close to the hydrophobic surface. © 2011 Mereghetti and Wad; licensee BioMed Central Ltd.

Salo-Ahen O.M.H.,Heidelberg Institute for Theoretical Studies HITS gGmbH | Salo-Ahen O.M.H.,Åbo Akademi University | Wade R.C.,Heidelberg Institute for Theoretical Studies HITS gGmbH
Proteins: Structure, Function and Bioinformatics | Year: 2011

Human thymidylate synthase (hTS) is an established anticancer target. It catalyses the production of 2'-deoxythymidine-5'-monophosphate, an essential building block for DNA synthesis. Because of the development of cellular drug resistance against current hTS inhibitors, alternative inhibition strategies are needed. hTS exists in two forms, active and inactive, defined by the conformation of the active-site (AS) loop, which carries the catalytic cysteine, C195. To investigate the mechanism of activation and inactivation, targeted molecular dynamics (TMD) simulations of the transitions between active and inactive states of hTS were performed. Analysis of changes in the dihedral angles in the AS loop during different TMD simulations revealed complex conformational transitions. Despite hTS being a homodimeric enzyme and the conformational transition significantly involving the dimer interface, the transition occurs in an asymmetric, sequential manner via an ensemble of pathways. In addition to C195, which reoriented during the simulations, other key residues in the rotation of the AS loop included W182 and R185. The interactions of the cognate bulky W182 residues at the dimer interface hindered the simultaneous twist of the AS loops in the hTS dimer. Interactions of R185, which is unique for hTS, with ligands at different allosteric sites affected the activation transition. In addition to providing insights into the activation/inactivation mechanism of hTS and how conformational transitions can occur in homodimeric proteins, our observations suggest that blocking of AS loop rotation by ligands binding in the large cavity between the loops could be one way to stabilize inactive hTS and inhibit the enzyme. © 2011 Wiley-Liss, Inc.

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