Exploring cavity dynamics in biomolecular systems

Background The internal cavities of proteins are dynamic structures and their dynamics may be associated with conformational changes which are required for the functioning of the protein. In order to study the dynamics of these internal protein cavities, appropriate tools are required that allow rapid identification of the cavities as well as assessment of their time-dependent structures. Results In this paper, we present such a tool and give results that illustrate the applicability for the analysis of molecular dynamics trajectories. Our algorithm consists of a pre-processing step where the structure of the cavity is computed from the Voronoi diagram of the van der Waals spheres based on coordinate sets from the molecular dynamics trajectory. The pre-processing step is followed by an interactive stage, where the user can compute, select and visualize the dynamic cavities. Importantly, the tool we discuss here allows the user to analyze the time-dependent changes of the components of the cavity structure. An overview of the cavity dynamics is derived by rendering the dynamic cavities in a single image that gives the cavity surface colored according to its time-dependent dynamics. Conclusion The Voronoi-based approach used here enables the user to perform accurate computations of the geometry of the internal cavities in biomolecules. For the first time, it is possible to compute dynamic molecular paths that have a user-defined minimum constriction size. To illustrate the usefulness of the tool for understanding protein dynamics, we probe the dynamic structure of internal cavities in the bacteriorhodopsin proton pump

Molecular cavity topological representation for pattern analysis: A NLP analogy-based word2vec method

© 2019 by the authors. Licensee MDPI, Basel, Switzerland. Cavity analysis in molecular dynamics is important for understanding molecular function. However, analyzing the dynamic pattern of molecular cavities remains a difficult task. In this paper, we propose a novel method to topologically represent molecular cavities by vectorization. First, a characterization of cavities is established through Word2Vec model, based on an analogy between the cavities and natural language processing (NLP) terms. Then, we use some techniques such as dimension reduction and clustering to conduct an exploratory analysis of the vectorized molecular cavity. On a real data set, we demonstrate that our approach is applicable to maintain the topological characteristics of the cavity and can find the change patterns from a large number of cavities

Visual cavity analysis in molecular simulations

Molecular surfaces provide a useful mean for analyzing interactions between biomolecules; such as identification and characterization of ligand binding sites to a host macromolecule. We present a novel technique, which extracts potential binding sites, represented by cavities, and characterize them by 3D graphs and by amino acids. The binding sites are extracted using an implicit function sampling and graph algorithms. We propose an advanced cavity exploration technique based on the graph parameters and associated amino acids. Additionally, we interactively visualize the graphs in the context of the molecular surface. We apply our method to the analysis of MD simulations of Proteinase 3, where we verify the previously described cavities and suggest a new potential cavity to be studied

Holistic corpus-based dialectology

This paper is concerned with sketching future directions for corpus-based dialectology. We advocate a holistic approach to the study of geographically conditioned linguistic variability, and we present a suitable methodology, 'corpusbased dialectometry', in exactly this spirit. Specifically, we argue that in order to live up to the potential of the corpus-based method, practitioners need to (i) abandon their exclusive focus on individual linguistic features in favor of the study of feature aggregates, (ii) draw on computationally advanced multivariate analysis techniques (such as multidimensional scaling, cluster analysis, and principal component analysis), and (iii) aid interpretation of empirical results by marshalling state-of-the-art data visualization techniques. To exemplify this line of analysis, we present a case study which explores joint frequency variability of 57 morphosyntax features in 34 dialects all over Great Britain

Interactive Visualization of Molecular Dynamics Simulation Data

Molecular Dynamics Simulations (MD) plays an essential role in the field of computational biology. The simulations produce extensive high-dimensional, spatio-temporal data describ-ing the motion of atoms and molecules. A central challenge in the field is the extraction and visualization of useful behavioral patterns from these simulations. Throughout this thesis, I collaborated with a computational biologist who works on Molecular Dynamics (MD) Simu-lation data. For the sake of exploration, I was provided with a large and complex membrane simulation. I contributed solutions to his data challenges by developing a set of novel visual-ization tools to help him get a better understanding of his simulation data. I employed both scientific and information visualization, and applied concepts of abstraction and dimensions projection in the proposed solutions. The first solution enables the user to interactively fil-ter and highlight dynamic and complex trajectory constituted by motions of molecules. The molecular dynamic trajectories are identified based on path length, edge length, curvature, and normalized curvature, and their combinations. The tool exploits new interactive visual-ization techniques and provides a combination of 2D-3D path rendering in a dual dimension representation to highlight differences arising from the 2D projection on a plane. The sec-ond solution introduces a novel abstract interaction space for Protein-Lipid interaction. The proposed solution addresses the challenge of visualizing complex, time-dependent interactions between protein and lipid molecules. It also proposes a fast GPU-based implementation that maps lipid-constituents involved in the interaction onto the abstract protein interaction space. I also introduced two abstract level-of-detail (LoD) representations with six levels of detail for lipid molecules and protein interaction. Finally, I proposed a novel framework consisting of four linked views: A time-dependent 3D view, a novel hybrid view, a clustering timeline, and a details-on-demand window. The framework exploits abstraction and projection to enable the user to study the molecular interaction and the behavior of the protein-protein interaction and clusters. I introduced a selection of visual designs to convey the behavior of protein-lipid interaction and protein-protein interaction through a unified coordinate system. Abstraction is used to present proteins in hybrid 2D space, and a projected tiled space is used to present both Protein-Lipid Interaction (PLI) and Protein-Protein Interaction (PPI) at the particle level in a heat-map style visual design. Glyphs are used to represent PPI at the molecular level. I coupled visually separable visual designs in a unified coordinate space. The result lets the user study both PLI and PPI separately, or together in a unified visual analysis framework

Geometric algorithms for cavity detection on protein surfaces

Macromolecular structures such as proteins heavily empower cellular processes or functions. These biological functions result from interactions between proteins and peptides, catalytic substrates, nucleotides or even human-made chemicals. Thus, several interactions can be distinguished: protein-ligand, protein-protein, protein-DNA, and so on. Furthermore, those interactions only happen under chemical- and shapecomplementarity conditions, and usually take place in regions known as binding sites. Typically, a protein consists of four structural levels. The primary structure of a protein is made up of its amino acid sequences (or chains). Its secondary structure essentially comprises -helices and -sheets, which are sub-sequences (or sub-domains) of amino acids of the primary structure. Its tertiary structure results from the composition of sub-domains into domains, which represent the geometric shape of the protein. Finally, the quaternary structure of a protein results from the aggregate of two or more tertiary structures, usually known as a protein complex. This thesis fits in the scope of structure-based drug design and protein docking. Specifically, one addresses the fundamental problem of detecting and identifying protein cavities, which are often seen as tentative binding sites for ligands in protein-ligand interactions. In general, cavity prediction algorithms split into three main categories: energy-based, geometry-based, and evolution-based. Evolutionary methods build upon evolutionary sequence conservation estimates; that is, these methods allow us to detect functional sites through the computation of the evolutionary conservation of the positions of amino acids in proteins. Energy-based methods build upon the computation of interaction energies between protein and ligand atoms. In turn, geometry-based algorithms build upon the analysis of the geometric shape of the protein (i.e., its tertiary structure) to identify cavities. This thesis focuses on geometric methods. We introduce here three new geometric-based algorithms for protein cavity detection. The main contribution of this thesis lies in the use of computer graphics techniques in the analysis and recognition of cavities in proteins, much in the spirit of molecular graphics and modeling. As seen further ahead, these techniques include field-of-view (FoV), voxel ray casting, back-face culling, shape diameter functions, Morse theory, and critical points. The leading idea is to come up with protein shape segmentation, much like we commonly do in mesh segmentation in computer graphics. In practice, protein cavity algorithms are nothing more than segmentation algorithms designed for proteins.Estruturas macromoleculares tais como as proteínas potencializam processos ou funções celulares. Estas funções resultam das interações entre proteínas e peptídeos, substratos catalíticos, nucleótideos, ou até mesmo substâncias químicas produzidas pelo homem. Assim, há vários tipos de interacções: proteína-ligante, proteína-proteína, proteína-DNA e assim por diante. Além disso, estas interações geralmente ocorrem em regiões conhecidas como locais de ligação (binding sites, do inglês) e só acontecem sob condições de complementaridade química e de forma. É também importante referir que uma proteína pode ser estruturada em quatro níveis. A estrutura primária que consiste em sequências de aminoácidos (ou cadeias), a estrutura secundária que compreende essencialmente por hélices e folhas , que são subsequências (ou subdomínios) dos aminoácidos da estrutura primária, a estrutura terciária que resulta da composição de subdomínios em domínios, que por sua vez representa a forma geométrica da proteína, e por fim a estrutura quaternária que é o resultado da agregação de duas ou mais estruturas terciárias. Este último nível estrutural é frequentemente conhecido por um complexo proteico. Esta tese enquadra-se no âmbito da conceção de fármacos baseados em estrutura e no acoplamento de proteínas. Mais especificamente, aborda-se o problema fundamental da deteção e identificação de cavidades que são frequentemente vistos como possíveis locais de ligação (putative binding sites, do inglês) para os seus ligantes (ligands, do inglês). De forma geral, os algoritmos de identificação de cavidades dividem-se em três categorias principais: baseados em energia, geometria ou evolução. Os métodos evolutivos baseiam-se em estimativas de conservação das sequências evolucionárias. Isto é, estes métodos permitem detectar locais funcionais através do cálculo da conservação evolutiva das posições dos aminoácidos das proteínas. Em relação aos métodos baseados em energia estes baseiam-se no cálculo das energias de interação entre átomos da proteína e do ligante. Por fim, os algoritmos geométricos baseiam-se na análise da forma geométrica da proteína para identificar cavidades. Esta tese foca-se nos métodos geométricos. Apresentamos nesta tese três novos algoritmos geométricos para detecção de cavidades em proteínas. A principal contribuição desta tese está no uso de técnicas de computação gráfica na análise e reconhecimento de cavidades em proteínas, muito no espírito da modelação e visualização molecular. Como pode ser visto mais à frente, estas técnicas incluem o field-of-view (FoV), voxel ray casting, back-face culling, funções de diâmetro de forma, a teoria de Morse, e os pontos críticos. A ideia principal é segmentar a proteína, à semelhança do que acontece na segmentação de malhas em computação gráfica. Na prática, os algoritmos de detecção de cavidades não são nada mais que algoritmos de segmentação de proteínas

Intensity-Based Skeletonization of CryoEM Gray-Scale Images Using a True Segmentation-Free Algorithm

Cryo-electron microscopy is an experimental technique that is able to produce 3D gray-scale images of protein molecules. In contrast to other experimental techniques, cryo-electron microscopy is capable of visualizing large molecular complexes such as viruses and ribosomes. At medium resolution, the positions of the atoms are not visible and the process cannot proceed. The medium-resolution images produced by cryo-electron microscopy are used to derive the atomic structure of the proteins in de novo modeling. The skeletons of the 3D gray-scale images are used to interpret important information that is helpful in de novo modeling. Unfortunately, not all features of the image can be captured using a single segmentation. In this paper, we present a segmentation-free approach to extract the gray-scale curve-like skeletons. The approach relies on a novel representation of the 3D image, where the image is modeled as a graph and a set of volume trees. A test containing 36 synthesized maps and one authentic map shows that our approach can improve the performance of the two tested tools used in de novo modeling. The improvements were 62 and 13 percent for Gorgon and DP-TOSS, respectively