AtomLbs: An Atom Based Convolutional Neural Network for Druggable Ligand Binding Site Prediction

Despite advances in drug research and development, there are few and ineffective treatments for a variety of diseases. Virtual screening can drastically reduce costs and accelerate the drug discovery process. Binding site identification is one of the initial and most important steps in structure-based virtual screening. Identifying and defining protein cavities that are likely to bind to a small compound is the objective of this task. In this research, we propose four different convolutional neural networks for predicting ligand-binding sites in proteins. A parallel optimized data pipeline is created to enable faster training of these neural network models on minimal hardware. The effectiveness of each method is assessed on well-established ligand binding site datasets. It is then compared with the state-of-the-art and widely used methods for ligand binding site identification. The result shows that our methods outperform most of the other methods and are comparable to the state-of-the-art methods

Biophysical insights into the high pressure sensitivity of biomolecules

Accurate folding and dynamics of biomolecules are substantially important for the functionality of living systems. As life can also be found in the realm of environmental extremes, biomolecules as well as their homo- and heterotypic interactions must withstand different environmental stresses including a wide range of temperature, pressure and salinity. For example, extreme conditions including high temperature, high hydrostatic pressure and high salinity can be found close to marine hydrothermal vents. Hence, adaptation strategies must exist to ensure life of extremophiles. Notably, globular proteins and double-stranded nucleic acids have been reported to be very pressure stable, whereas initial studies have shown that quaternary interactions of proteins and non-canonical structures of nucleic acids, being essential components of cellular entities, are rather pressure-sensitive. The present work shed light on the origin of the pressure sensitivity of the eukaryotic cytoskeleton by focusing on the components actin filaments and microtubules. More importantly, it addressed the issue of molecular strategies for pressure resistance. In particular, it focused on the role of accessory proteins of the cytoskeleton as well as the effects of macromolecular crowding and osmolytes, phenomena easily encountered inside cells. Further, the latter aspect was also investigated for a functional and temperature-sensitive ribonucleic acid hairpin known to regulate the gene expression in bacteria. To fundamentally understand the pressure effect on nucleic acids, the self-assembly reaction of guanosine-monophosphate as a single nucleotide was focus of the present work as well

Program and Proceedings: The Nebraska Academy of Sciences 1880-2010

PROGRAM FRIDAY, APRIL 23, 2010 REGISTRATION FOR ACADEMY, Lobby of Lecture wing, Olin Hall Aeronautics and Space Science, Session A, Olin 249 Aeronautics and Space Science, Session B, Olin 224 Chemistry and Physics, Section A, Chemistry, Olin A Collegiate Academy, Biology Session A, Olin B Collegiate Academy, Chemistry and Physics, Session A, Olin 324 Biological and Medical Sciences, Session A, Olin 112 Biological and Medical Sciences, Session B, Smith Callen Conference Center Chemistry and Physics, Section B, Physics, Planetarium History and Philosophy of Science, Olin 325 Junior Academy, Judges Check-In, Olin 219 Junior Academy, Senior High REGISTRATION, Olin Hall Lobby NWU Health and Sciences Graduate School Fair, Olin and Smith Curtiss Halls Junior Academy, Senior High Competition, Olin 124, Olin 131 Aeronautics and Space Science, Poster Session, Olin 249 Teaching of Science and Math, Olin 325 MAIBEN MEMORIAL LECTURE, OLIN B Dr. Mark Greip, Vice-Chair, Department of Chemistry, University of Nebraska-Lincoln LUNCH, PATIO ROOM, STORY STUDENT CENTER (pay and carry tray through cafeteria line, or pay at NAS registration desk) Aeronautics Group, Conestoga Room Anthropology, Olin 111 Biological and Medical Sciences, Session C, Olin 112 Biological and Medical Sciences, Session D, Smith Callen Conference Center Chemistry and Physics, Section A, Chemistry, Olin A Chemistry and Physics, Section B, Physics, Planetarium Collegiate Academy, Biology Session A, Olin B Collegiate Academy, Biology Session B, Olin 249 Collegiate Academy, Chemistry and Physics, Session A, Olin 324 Junior Academy, Judges Check-In, Olin 219 Junior Academy, Junior High REGISTRATION, Olin Hall Lobby Junior Academy, Senior High Competition, (Final), Olin 110 Earth Science, Olin 224 Junior Academy, Junior High Competition, Olin 124, Olin 131 NJAS Board/Teacher Meeting, Olin 219 Junior Academy, General Awards Presentations, Smith Callen Conference Center BUSINESS MEETING, OLIN B SOCIAL HOUR for Members, Spouses, and Guests First United Methodist Church, 2723 N 50th Street, Lincoln, NE ANNUAL BANQUET and Presentation of Awards and Scholarships First United Methodist Church, 2723 N 50th Street, Lincoln, N

A COMPUTATIONAL APPROACH FOR ACCESSING PHOSPHORYLATED RESPONSE REGULATOR CONFORMATIONS AND SIGNALING COMPLEXES INVOLVING THE FUNGAL PHOSPHORELAY PROTEIN YPD1

Two-component signaling is the primary means by which bacteria, archaea and certain eukaryotes sense and respond to their environments. Signal transfer proceeds through sequential His-to-Asp phosphorylation of upstream histidine kinases and downstream response regulators. These systems share highly modular designs and have been incorporated into a myriad of cellular processes. The highly labile chemical natures of phosphoaspartate and phosphohistidine lead to relatively short experimental life-times, making study of the modified signaling proteins challenging. The focus of this research was to develop computational and experimental approaches for characterizing phosphorylated two-component signaling proteins. Following an introductory chapter, the first experimental section presents a computational technique for simulating the activation of individual response regulator proteins. This is accomplished using known experimental data on conserved active site chemistry to define a common set of restraints to drive each simulation. The protocol was verified on five genetically diverse response regulators with known experimental structures. The second section applies this principle to signaling complexes to study the effects of phosphorylation on protein- protein interactions within the Saccharomyces cerevisiae osmoregulatory signaling system. The third section describes the experimental characterization of a specific signaling complex from Saccharomyces cerevisiae between the response regulator Ssk1 and a point mutant (G68Q) of the histidine phosphotransfer protein Ypd1 using X-ray crystallography. This mutation occurs near the active site of both proteins and appears to interfere with phosphotransfer. Further in silico studies were performed to observe the role of G68 in catalysis of phosphotransfer

Washington University Senior Undergraduate Research Digest (WUURD), Spring 2018

From the Washington University Office of Undergraduate Research Digest (WUURD), Vol. 13, 05-01-2018. Published by the Office of Undergraduate Research. Joy Zalis Kiefer, Director of Undergraduate Research and Associate Dean in the College of Arts & Scien

Computational Approaches to Drug Profiling and Drug-Protein Interactions

Despite substantial increases in R&D spending within the pharmaceutical industry, denovo drug design has become a time-consuming endeavour. High attrition rates led to a long period of stagnation in drug approvals. Due to the extreme costs associated with introducing a drug to the market, locating and understanding the reasons for clinical failure is key to future productivity. As part of this PhD, three main contributions were made in this respect. First, the web platform, LigNFam enables users to interactively explore similarity relationships between ‘drug like’ molecules and the proteins they bind. Secondly, two deep-learning-based binding site comparison tools were developed, competing with the state-of-the-art over benchmark datasets. The models have the ability to predict offtarget interactions and potential candidates for target-based drug repurposing. Finally, the open-source ScaffoldGraph software was presented for the analysis of hierarchical scaffold relationships and has already been used in multiple projects, including integration into a virtual screening pipeline to increase the tractability of ultra-large screening experiments. Together, and with existing tools, the contributions made will aid in the understanding of drug-protein relationships, particularly in the fields of off-target prediction and drug repurposing, helping to design better drugs faster

STRUCTURAL ORIGINS OF PRESSURE EFFECTS IN PROTEINS

The molecular mechanisms of chemical and heat denaturation of proteins are relatively well established; those of pressure unfolding are not. Volume is the conjugate variable of pressure; it is the fundamental thermodynamic variable that governs the pressure sensitivity of proteins. Cavities that are present in the native state and absent in the unfolded state are thought to contribute significantly to the change in volume upon unfolding (∆V). Staphylococcal nuclease was used to examine the role of cavities systematically. The wild-type protein has a small cavity in its hydrophobic core, comparable in volume to a water molecule. Artificial cavities were generated by substitution of internal hydrophobic residues to Ala. Substitutions of small residues with large ones were used to eliminate the natural cavity. Substitutions to polar residues were used to affect the hydration state of cavities. For 27 variants studied, (a) crystal structures, (b) thermodynamic stabilities using chemical denaturation, and (c) ∆V of unfolding measured by pressure denaturation monitored with Trp-fluorescence and NMR spectroscopy were obtained. In general, the cavities did not affect the structure. The cavities were large enough to hold several waters, but these were only detected in the cavities lined with polar groups. The measured ∆V of variants was always larger than for the wild-type. A near-linear correlation between the ∆V measured experimentally and the one calculated from structures illustrate the importance of cavities in pressure sensitivity. A correlation between measured ∆V and thermodynamic stability (∆G°) suggests that 1 kcal/mol is lost per 11 mL/mol of increased void volume. This study demonstrates that cavities contribute significantly towards the pressure sensitivity of proteins and can modulate the hydration and structural fluctuations of proteins