An in-silico study: Investigating small molecule modulators of bio-molecular interactions

Small molecule inhibitors are commonly used to target protein targets that assist in the spread of diseases such as AIDS, cancer and deadly forms of influenza. Despite drug companies spending millions on R&D, the number of drugs that pass clinical trials is limited due to difficulties in engineering optimal non-covalent interactions. As many protein targets have the ability to rapidly evolve resistance, there is an urgent need for methods that rapidly identify effective new compounds. The thermodynamic driving force behind most biochemical reactions is known as the Gibbs free energy and it contains opposing dynamic and structural components that are known as the entropy (ΔS°) and enthalpy (ΔH°) respectively. ΔG° = ΔH° - TΔS°. Traditionally, drug design focussed on complementing the shape of an inhibitor to the binding cavity to optimise ΔG° favourability. However, this approach neglects the entropic contribution and phenomena such as Entropy-Enthalpy Compensation (EEC) often result in favourable bonding interactions not improving ΔG°, due to entropic unfavorability. Similarly, attempts to optimise inhibitor entropy can also have unpredictable results. Experimental methods such as ITC report on global thermodynamics, but have difficulties identifying the underlying molecular rationale for measured values. However, computational techniques do not suffer from the same limitations. MUP-I can promiscuously bind panels of hydrophobic ligands that possess incremental structural differences. Thus, small perturbations to the system can be studied through various in silico approaches. This work analyses the trends exhibited across these panels by examining the dynamic component via the calculation of per-unit entropies of protein, ligand and solvent. Two new methods were developed to assess the translational and rotational contributions to TΔS°, and a protocol created to study ligand internalisation. Synthesising this information with structural data obtained from spatial data on the binding cavity, intermolecular contacts and H-bond analysis allowed detailed molecular rationale for the global thermodynamic signatures to be derived

Chemistry & Chemical Biology 2013 APR Self-Study & Documents

UNM Chemistry & Chemical Biology APR self-study report, review team report, response to review report, and initial action plan for Spring 2013, fulfilling requirements of the Higher Learning Commission

Structural Diversity of Biological Ligands and their Binding Sites in Proteins

The phenomenon of molecular recognition, which underpins almost all biological processes, is dynamic, complex and subtle. Establishing an interaction between a pair of molecules involves mutual structural rearrangements guided by a highly convoluted energy landscape, the accurate mapping of which continues to elude us. The analysis of interactions between proteins and small molecules has been a focus of intense interest for many years, offering as it does the promise of increased insight into many areas of biology, and the potential for greatly improved drug design methodologies. Computational methods for predicting which types of ligand a given protein may bind, and what conformation two molecules will adopt once paired, are particularly sought after. The work presented in this thesis aims to quantify the amount of structural variability observed in the ways in which proteins interact with ligands. This diversity is considered from two perspectives: to what extent ligands bind to different proteins in distinct conformations, and the degree to which binding sites specific for the same ligand have different atomic structures. The first study could be of value to approaches which aim to predict the bound pose of a ligand, since by cataloguing the range of conformations previously observed, it may be possible to better judge the biological likelihood of a newly predicted molecular arrangement. The findings show that several common biological ligands exhibit considerable conformational diversity when bound to proteins. Although binding in predominantly extended conformations, the analysis presented here highlights several cases in which the biological requirements of a given protein force its ligand to adopt a highly compact form. Comparing the conformational diversity observed within several protein families, the hypothesis that homologous proteins tend to bind ligands in a similar arrangement is generally upheld, but several families are identified in which this is demonstrably not the case. Consideration of diversity in the binding site itself, on the other hand, may be useful in guiding methods which search for binding sites in uncharacterised protein structures: identifying those regions of known sites which are less variable could help to focus the search only on the most important features. Analysis of the diversity of a non-redundant dataset of adenine binding sites shows that a small number of key interactions are conserved, with the majority of the fragment environment being highly variable. Just as ligand conformation varies between protein families, so the degree of binding site diversity is observed to be significantly higher in some families than others. Taken together, the results of this work suggest that the repertoire of strategies produced by nature for the purposes of molecular recognition are extremely extensive. Moreover, the importance of a given ligand conformation or pattern of interaction appears to vary greatly depending on the function of the particular group of proteins studied. As such, it is proposed that diversity analysis may form a significant part of future large-scale studies of ligand-protein interactions

The Prague School and Theories of Structure

Diese Reihe untersucht Gemeinsamkeiten und Unterschiede von Natur- und Geisteswissenschaftlichen. Das Konzept des »Einflusses« bzw. des »gegenseitigen Einflusses« soll zugunsten eines dynamischeren Konzepts des »Interfacing« (Verbindung/Vernetzung) hinterfragt werden. Ein grundlegender Ausgangspunkt ist die Erkenntnis, dass die beiden Wissenssphären, die geistes- und die naturwissenschaftliche, häufig zur gleichen Zeit neue Untersuchungsmodelle entwickeln und damit auf komplexe wissenschaftliche und kulturelle Phänomene reagieren. Das Konzept des »Interfacing« impliziert eine integrierte Sicht neuer Wissensgebiete in neuen Kontexten. Nicht länger an der traditionellen Vorstellung von »Ursache und Wirkung« gebunden, impliziert der Isomorphismus Gleichzeitigkeit statt Konsequentialität. Nicht immer beeinflusst die eine Sphäre die andere; Isomorphismus impliziert gemeinsame Entdeckungen, durch die beide Bereichen zur gleichen Zeit neue investigative Modelle und Darstellungssysteme entwickeln. Dialog und gegenseitiges Verständnis zwischen den beiden sogenannten »zwei Kulturen« werden so stimuliert. Wichtige Forschungsbereiche sind Interfacing-Modelle und Paradigmen in den Natur- und Geisteswissenschaften, kulturell bedingte Darstellungen von Naturwissenschaft und Technologie, wissenschaftliche Entdeckungen und narrative Diskurse, Lebenserinnerungen von Wissenschaftlerinnen und Wissenschaftlern, das Überschreiten von Grenzen zwischen Natur- und Geisteswissenschaft durch Lernen sowie die Bereicherung der Geisteswissenschaften durch angewandte Naturwissenschaften, einschließlich der Informationstechnologien. Die Reihe umfasst sowohl Monographien als auch Essaysammlungen in englischer, deutscher, französischer und italienischer Sprache. Das Nebeneinander verschiedener Sprachen zeugt von der Intention von Herausgeberschaft und wissenschaftlichem Beirats, ein integriertes Wissen aus europäischer Perspektive herauszubilden

Macroevolution: Explanation, Interpretation and Evidence

info:eu-repo/semantics/publishedVersio

Evolutionary genomics : statistical and computational methods

This open access book addresses the challenge of analyzing and understanding the evolutionary dynamics of complex biological systems at the genomic level, and elaborates on some promising strategies that would bring us closer to uncovering of the vital relationships between genotype and phenotype. After a few educational primers, the book continues with sections on sequence homology and alignment, phylogenetic methods to study genome evolution, methodologies for evaluating selective pressures on genomic sequences as well as genomic evolution in light of protein domain architecture and transposable elements, population genomics and other omics, and discussions of current bottlenecks in handling and analyzing genomic data. Written for the highly successful Methods in Molecular Biology series, chapters include the kind of detail and expert implementation advice that lead to the best results. Authoritative and comprehensive, Evolutionary Genomics: Statistical and Computational Methods, Second Edition aims to serve both novices in biology with strong statistics and computational skills, and molecular biologists with a good grasp of standard mathematical concepts, in moving this important field of study forward

Using MapReduce Streaming for Distributed Life Simulation on the Cloud

Distributed software simulations are indispensable in the study of large-scale life models but often require the use of technically complex lower-level distributed computing frameworks, such as MPI. We propose to overcome the complexity challenge by applying the emerging MapReduce (MR) model to distributed life simulations and by running such simulations on the cloud. Technically, we design optimized MR streaming algorithms for discrete and continuous versions of Conway’s life according to a general MR streaming pattern. We chose life because it is simple enough as a testbed for MR’s applicability to a-life simulations and general enough to make our results applicable to various lattice-based a-life models. We implement and empirically evaluate our algorithms’ performance on Amazon’s Elastic MR cloud. Our experiments demonstrate that a single MR optimization technique called strip partitioning can reduce the execution time of continuous life simulations by 64%. To the best of our knowledge, we are the first to propose and evaluate MR streaming algorithms for lattice-based simulations. Our algorithms can serve as prototypes in the development of novel MR simulation algorithms for large-scale lattice-based a-life models.https://digitalcommons.chapman.edu/scs_books/1014/thumbnail.jp

Evolutionary Genomics

This open access book addresses the challenge of analyzing and understanding the evolutionary dynamics of complex biological systems at the genomic level, and elaborates on some promising strategies that would bring us closer to uncovering of the vital relationships between genotype and phenotype. After a few educational primers, the book continues with sections on sequence homology and alignment, phylogenetic methods to study genome evolution, methodologies for evaluating selective pressures on genomic sequences as well as genomic evolution in light of protein domain architecture and transposable elements, population genomics and other omics, and discussions of current bottlenecks in handling and analyzing genomic data. Written for the highly successful Methods in Molecular Biology series, chapters include the kind of detail and expert implementation advice that lead to the best results. Authoritative and comprehensive, Evolutionary Genomics: Statistical and Computational Methods, Second Edition aims to serve both novices in biology with strong statistics and computational skills, and molecular biologists with a good grasp of standard mathematical concepts, in moving this important field of study forward

Proceedings of the 21st International Congress of Aesthetics, Possible Worlds of Contemporary Aesthetics Aesthetics Between History, Geography and Media

The Faculty of Architecture, University of Belgrade and the Society for Aesthetics of Architecture and Visual Arts of Serbia (DEAVUS) are proud to be able to organize the 21st ICA Congress on “Possible Worlds of Contemporary Aesthetics: Aesthetics Between History, Geography and Media”. We are proud to announce that we received over 500 submissions from 56 countries, which makes this Congress the greatest gathering of aestheticians in this region in the last 40 years. The ICA 2019 Belgrade aims to map out contemporary aesthetics practices in a vivid dialogue of aestheticians, philosophers, art theorists, architecture theorists, culture theorists, media theorists, artists, media entrepreneurs, architects, cultural activists and researchers in the fields of humanities and social sciences. More precisely, the goal is to map the possible worlds of contemporary aesthetics in Europe, Asia, North and South America, Africa and Australia. The idea is to show, interpret and map the unity and diverseness in aesthetic thought, expression, research, and philosophies on our shared planet. Our goal is to promote a dialogue concerning aesthetics in those parts of the world that have not been involved with the work of the International Association for Aesthetics to this day. Global dialogue, understanding and cooperation are what we aim to achieve. That said, the 21st ICA is the first Congress to highlight the aesthetic issues of marginalised regions that have not been fully involved in the work of the IAA. This will be accomplished, among others, via thematic round tables discussing contemporary aesthetics in East Africa and South America. Today, aesthetics is recognized as an important philosophical, theoretical and even scientific discipline that aims at interpreting the complexity of phenomena in our contemporary world. People rather talk about possible worlds or possible aesthetic regimes rather than a unique and consistent philosophical, scientific or theoretical discipline