Anna Katharina Dehof

BALL - biochemical algorithms library 1.3

BackgroundThe Biochemical Algorithms Library (BALL) is a comprehensive rapid application development framework for structural bioinformatics. It provides an extensive C++ class library of data structures and algorithms for molecular modeling and structural bioinformatics. Using BALL as a programming toolbox does not only allow to greatly reduce application development times but also helps in ensuring stability and correctness by avoiding the error-prone reimplementation of complex algorithms and replacing them with calls into the library that has been well-tested by a large number of developers. In the ten years since its original publication, BALL has seen a substantial increase in functionality and numerous other improvements.ResultsHere, we discuss BALLs current functionality and highlight the key additions and improvements: support for additional file formats, molecular edit-functionality, new molecular mechanics force fields, novel energy minimization techniques, docking algorithms, and support for cheminformatics.ConclusionsBALL is available for all major operating systems, including Linux, Windows, and MacOS X. It is available free of charge under the Lesser GNU Public License (LPGL). Parts of the code are distributed under the GNU Public License (GPL). BALL is available as source code and binary packages from the project web site at http://www.ball-project.org. Recently, it has been accepted into the debian project; integration into further distributions is currently pursued.

Human SAP18 mediates assembly of a splicing regulatory multiprotein complex via its ubiquitin-like fold

RNPS1, Acinus, and SAP18 form the apoptosis- and splicing-associated protein (ASAP) complex, which is also part of the exon junction complex. Whereas RNPS1 was originally identified as a general activator of mRNA processing, all three proteins have been found within functional spliceosomes. Both RNPS1 and Acinus contain typical motifs of splicing regulatory proteins including arginine/serine-rich domains. Due to the absence of such structural features, however, a function of SAP18 in splicing regulation is completely unknown. Here we have investigated splicing regulatory activities of the ASAP components. Whereas a full-length Acinus isoform displayed only limited splicing regulatory activity, both RNPS1 and, surprisingly, SAP18 strongly modulated splicing regulation. Detailed mutational analysis and three-dimensional modeling data revealed that the ubiquitin-like fold of SAP18 was required for efficient splicing regulatory activity. Coimmunoprecipitation and immunofluorescence experiments demonstrated that SAP18 assembles a nuclear speckle-localized splicing regulatory multiprotein complex including RNPS1 and Acinus via its ubiquitin-like fold. Our results therefore suggest a novel function of SAP18 in splicing regulation.

Instruction of haematopoietic lineage choices, evolution of transcriptional landscapes and cancer stem cell hierarchies derived from an AML1-ETO mouse model

The t(8;21) chromosomal translocation activates aberrant expression of the AML1‐ETO (AE) fusion protein and is commonly associated with core binding factor acute myeloid leukaemia (CBF AML). Combining a conditional mouse model that closely resembles the slow evolution and the mosaic AE expression pattern of human t(8;21) CBF AML with global transcriptome sequencing, we find that disease progression was characterized by two principal pathogenic mechanisms. Initially, AE expression modified the lineage potential of haematopoietic stem cells (HSCs), resulting in the selective expansion of the myeloid compartment at the expense of normal erythro‐ and lymphopoiesis. This lineage skewing was followed by a second substantial rewiring of transcriptional networks occurring in the trajectory to manifest leukaemia. We also find that both HSC and lineage‐restricted granulocyte macrophage progenitors (GMPs) acquired leukaemic stem cell (LSC) potential being capable of initiating and maintaining the disease. Finally, our data demonstrate that long‐term expression of AE induces an indolent myeloproliferative disease (MPD)‐like myeloid leukaemia phenotype with complete penetrance and that acute inactivation of AE function is a potential novel therapeutic option.

Real-Time Ray Tracing of Complex Molecular Scenes

Molecular visualization is one of the cornerstones in structural bioinformatics and related fields. Today, rasterization is typically used for the interactive display of molecular scenes, while ray tracing aims at generating high-quality images, taking typically minutes to hours to generate and requiring the usage of an external off-line program. Recently, real-time ray tracing evolved to combine the interactivity of rasterization-based approaches with the superb image quality of ray tracing techniques. We demonstrate how real-time ray tracing integrated into a molecular modelling and visualization tool allows for better understanding of the structural arrangement of biomolecules and natural creation of publication-quality images in real-time. However, unlike most approaches, our technique naturaly integrates into the full-featured molecular modelling and visualization tool BALLView, seamlessly extending a standard workflow with interactive high-quality rendering.

Automated bond order assignment as an optimization problem

MOTIVATION Numerous applications in Computational Biology process molecular structures and hence strongly rely not only on correct atomic coordinates but also on correct bond order information. For proteins and nucleic acids, bond orders can be easily deduced but this does not hold for other types of molecules like ligands. For ligands, bond order information is not always provided in molecular databases and thus a variety of approaches tackling this problem have been developed. In this work, we extend an ansatz proposed by Wang et al. that assigns connectivity-based penalty scores and tries to heuristically approximate its optimum. In this work, we present three efficient and exact solvers for the problem replacing the heuristic approximation scheme of the original approach: an A*, an ILP and an fixed-parameter approach (FPT) approach. RESULTS We implemented and evaluated the original implementation, our A*, ILP and FPT formulation on the MMFF94 validation suite and the KEGG Drug database. We show the benefit of computing exact solutions of the penalty minimization problem and the additional gain when computing all optimal (or even suboptimal) solutions. We close with a detailed comparison of our methods. AVAILABILITY The A* and ILP solution are integrated into the open-source C++ LGPL library BALL and the molecular visualization and modelling tool BALLView and can be downloaded from our homepage www.ball-project.org. The FPT implementation can be downloaded from http://bio.informatik.uni-jena.de/software/.

Measuring properties of molecular surfaces using ray casting

Molecular geometric properties, such as volume, exposed surface area, and occurrence of internal cavities, are important inputs to many applications in molecular modeling. In this work we describe a very general and highly efficient approach for the accurate computation of such properties, which is applicable to arbitrary molecular surface models. The technique relies on a high performance ray casting framework that can be easily adapted to the computation of further quantities of interest at interactive speed, even for huge models.

ProteinScanAR - An Augmented Reality Web Application for High School Education in Biomolecular Life Sciences

Understanding protein structures is a crucial step in creating molecular insight for researchers as well as students and pupils. The enormous scaling gap between an atomic point of view and objects in daily life hampers developing an intuitive relation between them. Especially for high school students, it can be difficult to understand the spatial relations of a protein structure. Due to lack of direct imaging techniques, molecules can only be explored by studying abstract molecular models. Here, the use of Augmented reality (AR) techniques has proven to strongly improve structural perception. In this work we present ProteinScanAR, an augmented reality framework for biomolecular education that allows connecting virtual and real worlds intuitively, and thus enables focusing on the scientific or educational content. Special attention was taken to guarantee implementational and technical requirements as general and simple as possible to alleviate application in nonexpert computer settings. The ProteinScanAR framework is freely available under the GNU Public License (GPL).

NightShift: NMR shift inference by general hybrid model training - a framework for NMR chemical shift prediction

BackgroundNMR chemical shift prediction plays an important role in various applications in computational biology. Among others, structure determination, structure optimization, and the scoring of docking results can profit from efficient and accurate chemical shift estimation from a three-dimensional model.A variety of NMR chemical shift prediction approaches have been presented in the past, but nearly all of these rely on laborious manual data set preparation and the training itself is not automatized, making retraining the model, e.g., if new data is made available, or testing new models a time-consuming manual chore.ResultsIn this work, we present the framework NightShift (NMR Shift Inference by General Hybrid Model Training), which enables automated data set generation as well as model training and evaluation of protein NMR chemical shift prediction.In addition to this main result - the NightShift framework itself - we describe the resulting, automatically generated, data set and, as a proof-of-concept, a random forest model called Spinster that was built using the pipeline.ConclusionBy demonstrating that the performance of the automatically generated predictors is at least en par with the state of the art, we conclude that automated data set and predictor generation is well-suited for the design of NMR chemical shift estimators.The framework can be downloaded from https://bitbucket.org/akdehof/nightshift. It requires the open source Biochemical Algorithms Library (BALL), and is available under the conditions of the GNU Lesser General Public License (LGPL). We additionally offer a browser-based user interface to our NightShift instance employing the Galaxy framework via https://ballaxy.bioinf.uni-sb.de/.

PresentaBALL — A powerful package for presentations and lessons in structural biology

Structural biology is based on an important observation: the function of a biomolecule is determined by its three-dimensional structure and its physico-chemical properties. Hence, visualization, modeling, and simulation of molecular structures and of their properties are crucial tools of the field. Typically, the graphical interfaces to molecular modeling packages are aimed at domain experts with significant experience and require an extensive learning period. But in many scenarios, such as teaching, presentations, and demonstrations, it would be highly preferable to have an intuitive environment for showcasing molecular functionality. Ideally, it should support simple preparation of the presentations as well as their convenient display. To keep the user interface simple and focused, the environment should be particularly adapted to the processing of molecular structures. Here, we present such a presentation framework, called PresentaBALL, which uses established web technology standards to provide a freely configurable browser-based interface into the extensive modeling and visualization capabilities of the Biochemical Algorithms Library (BALL). The web interface is embedded into BALLs graphical frontend BALLView, and provides complete, interactive access to the loaded molecular data. PresentaBALL enables researchers in biology with basic knowledge in HTML, JavaScript, or Python to easily setup academic tutorials, demonstrations, or scientific presentations and lectures with 3D structure content and interactive workflows. Owing to its flexible design, other modern forms of teaching and presentation, such as massive open online courses (MOOC) can also use PresentaBALL as their core component. PresentaBALL is licensed under the GNU Public License (GPL) and will be made available in BALL/BALLView, starting with the upcoming release (1.5).