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ItemNew Biology from Natural Metamorphosis of a Conventional Class of Enzymes(Georgia Institute of Technology, 2011-11-15) Schimmel, PaulA group of enzymes known as aminoacyl tRNA synthetases interpret genetic information through catalysis of aminoacylation reactions that establish the genetic code. Errors of interpretation are corrected by a universal mechanism that is facilitated by novel domains incorporated into these same enzymes. This error-correcting activity is closely associated with the beginnings of living organism, and defects in this activity lead to disease and even lethality. The paradigm of incorporating novel domain additions to develop a specialized activity has been expanded in higher organisms where these domain additions are incorporated into a large library of naturally occurring new structures arising from alternative splicing and proteolysis. This metamorphosis into new structures gives rise to a diversity of new functions that go beyond translation of genetic information. Investigations of several of these structural metamorphs have uncovered new biology that has clinical applications.
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ItemProtein Folding Inside Cells and Other Crowded Environments(Georgia Institute of Technology, 2011-11-08) Gruebele, MartinComputer simulations are reaching the point where folding of small proteins in vitro can be successfully achieved ‘ab initio’ by molecular dynamics. Experiments can help further calibrate simulations, and I will discuss two examples. Experiments can also move forward to study protein dynamics in complex environment, such as the interior of the cell. There, modulation of the energy landscape and local viscosity can affect protein stability and folding kinetics. I will discuss experimental examples. The ultimate question, which cannot be answered yet, is whether cells evolved to gainfully modulate protein landscapes after post translational folding and modification, or whether microenvironments in the cell just provide stochastic modulation.
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ItemGOAP: A Generalized Orientation-Dependent, All-Atom Statistical Potential for Protein Structure Prediction(Georgia Institute of Technology, 2011-10) Zhou, Hongyi ; Skolnick, JeffreyAn accurate scoring function is a key component for successful protein structure prediction. To address this important unsolved problem, we develop a generalized orientation and distance-dependent all-atom statistical potential. The new statistical potential, generalized orientation-dependent all-atom potential (GOAP), depends on the relative orientation of the planes associated with each heavy atom in interacting pairs. GOAP is a generalization of previous orientation-dependent potentials that consider only representative atoms or blocks of side-chain or polar atoms. GOAP is decomposed into distance- and angle-dependent contributions. The DFIRE distance-scaled finite ideal gas reference state is employed for the distance-dependent component of GOAP. GOAP was tested on 11 commonly used decoy sets containing 278 targets, and recognized 226 native structures as best from the decoys, whereas DFIRE recognized 127 targets. The major improvement comes from decoy sets that have homology-modeled structures that are close to native (all within ∼4.0 Å) or from the ROSETTA ab initio decoy set. For these two kinds of decoys, orientation-independent DFIRE or only side-chain orientation-dependent RWplus performed poorly. Although the OPUS-PSP block-based orientation-dependent, side-chain atom contact potential performs much better (recognizing 196 targets) than DFIRE, RWplus, and dDFIRE, it is still ∼15% worse than GOAP. Thus, GOAP is a promising advance in knowledge-based, all-atom statistical potentials. GOAP is available for download at http://cssb.biology.gatech.edu/GOAP.
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ItemCheminformatic and assay-performance profiling of small-molecule screening collections(Georgia Institute of Technology, 2011-05-17) Clemons, Paul A .Quantitative decisions about properties and behavior of compound sets are important in building screening collections for smallmolecule probes and drugs. Decisions about individual compounds typically dominate such discussions: individual compounds pass or fail filtering rules, individual compounds hit or not in assays, etc. In this presentation, we focus on analyses directed at sets of compounds rather than individual members. We start with bioinformatic analysis of natural product and drug targets that motivates the need for new sources of synthetic small molecules. Next, we use sets of molecules from 3 sources (commercial, natural, academic) to show that different computed chemical properties (cheminformatic profiles) provide different chemical intuition about diversity of compound sets, and how quantifying these relationships can provide guidance to synthetic chemists. In the second part, we show that arrays of biological performance measurements (assay-performance profiles) can be used, instead of chemical structure, as a basis for small-molecule similarity, with implications for target identification and lead hopping. To illustrate connections between computed and measured properties, we describe a structured small-molecule profiling experiment in which 15,000 compounds were exposed to 100 different protein-binding assays. We show how different computed molecular complexity and shape descriptors accord with specificity of performance in protein-binding assays. Finally, using the same dataset, we introduce a measure of assay-performance diversity based on information entropy, and show how it might be used to judge relationships between computed properties and performance diversity of compound collections.
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ItemHow do proteins do all of that as seen by hydrogen exchange. Protein folding, GroEL function, lipoprotein structure(Georgia Institute of Technology, 2011-05-10) Englander, S. WalterThe talk will illustrate the use of hydrogen exchange methods to learn about biophysical properties and functional behaviors of protein molecules. Hydrogen exchange has been measured by older tritium exchange techniques, by 2D NMR, and most recently by mass spectrometry. Examples of applications will illustrate how each method provides specific advantages for different applications. Topics to be considered include how proteins fold, and how GroEL helps proteins to fold. Also recent progress in extending hydrogen exchange to the study of large and even insoluble protein systems using mass spectrometry will be shown.
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ItemDismantling Complex Problems into their Simple Substrates: From Embryonic Stems Cells to Global Peace(Georgia Institute of Technology, 2011-03-09) Zucker, Howard A.In the constantly changing world that we all live in today, problems appear to surface that have many faces depending upon one’s vantage point. At times it may be possible to distill some of the complexities into smaller subunits that are easier to tackle. Today’s lecture will look at several examples and personal experiences with these dilemmas. Included in the presentation is a discussion on how a child’s toy can help improve health for millions of illiterate people, why a device in the hands of billions can guarantee safety of the pharmaceutical supply chain, the way a few simple questions can determine whether billions spent on peace are actually making a difference and the applicability of an accepted medical practice to expanding the use of stem cells. In addition, a discussion on how historical examples can be used to help develop national vaccination programs and can lay a foundation for tissue engineering research, as well as how research into one biological system can possibly solve many medical problems, and at the same time help contribute to alternative energy sources
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ItemEvolution: from atoms to organisms(Georgia Institute of Technology, 2011-02-15) Shakhnovich, EugeneModern Biology is deeply rooted in Darwinian principles of mutations and selection. Population Genetics aims to address the effects of mutations and selection on populations in a quantitative way within the basic paradigm of ‘’fitness landscape’’, which postulates how genotypicchanges affect phenotype (e.g., fitness or growth rate of an organism or a tissue). No clear connection between the fitness effects of mutations and their effect on molecular properties of proteins has been systematically established – proteins are still treated as ‘’black boxes’’ in most population and organism level studies of evolution. In this talk I will present a systematic theoretical and experimental effort in our lab to go beyond this paradigm by developing multiscale models which relate molecular properties of proteins (their folding, function and interactions) to fitness of carrier organisms. By analyzing such models (both in simulations and analytically) we derived distribution of proteins stabilities which is very close to experimentally observed ones and predict its dependence of mutation rates and population size, linking ecology and molecular biophysics. Further we predicted and found correlation between protein stabilities and their abundances in cells as well as between protein abundances and strength of their interactions with other proteins. We discovered a universal physics-based speed limit on mutation rates in all organisms – ~6 missense mutations per essential part of the genome per replication. Further, we systematically experimentally probe fitness landscape by making controllable biophysical changes in proteins (varying stability and folding rates by mutations and abundances by manipulating upstream regions) with subsequent incorporation of mutant genes into E.coli chromosome and evaluating fitness of mutant strains in competition with wild-type. Our experiments confirm basic features of physics-based fitness landscape and add important new insights on how to make them more comprehensive and accurate.
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ItemSynthetic Antigen Binders: Novel applications for Structural and Cell Biology(Georgia Institute of Technology, 2011-02-08) Kossiakoff, Anthony A.Synthetic Antigen Binders (sABs) are a new class of antibody-based reagents engineered using novel phage display libraries. Using the power of phage display selection, it is possible generate sABs that : 1) target specific regions on the surface of a protein, 2) recognize specific conformational or oligomeric states, 3) induce conformational changes, and 4) capture and stabilize multi-protein complexes. Using these attributes, we can generate sABs that have their own functional properties and when introduced into cells can alter biological processes in defined ways. We have also employed them as crystallization chaperones to capture proteins in their most relevant states. As an example, the structure of the full-length KcsA potassium channel in both its closed and open states will be discussed. Further, we have also developed a cell delivery system that provides for introducing fully functional sABs into the cytoplasm for live cell imaging applications and to selectively alter cellular function.
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ItemChemical genetic investigations of protein and lipid kinase signaling(Georgia Institute of Technology, 2011-01-25) Shokat, KevanKinases are highly regulated enzymes with diverse mechanisms controlling their catalytic output. Inhibitor discovery efforts for kinases have produced ATP-competitive compounds, allosteric regulators, irreversible binders, and highly specific inhibitors. These distinct classes of small molecules have revealed many novel aspects about kinase-mediated signaling and some have progressed from simple tool compounds into clinically validated therapeutics. My presentation will explore several small-molecule inhibitors for kinases highlighting elaborate mechanisms by which kinase function is modulated. A complete surprise of targeted kinase drug discovery has been discovery of ATP-competitive inhibitors that behave as agonists, rather than antagonists, of their direct kinase target. These studies hint at a connection between ATP binding site occupancy and networks of communication that are independent of kinase catalysis. Indeed, kinase inhibitors have been found that induce changes in protein localization, protein-protein interactions, and even enhancement of catalytic activity of the target kinase. The relevance of these findings to the therapeutic efficacy of kinase inhibitors and to the future identification of new classes of drug targets will be discussed.
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ItemBrownian dynamics simulation of macromolecule diffusion in a protocell(Georgia Institute of Technology, 2011) Ando, Tadashi ; Skolnick, JeffreyThe interiors of all living cells are highly crowded with macro molecules, which differs considerably the thermodynamics and kinetics of biological reactions between in vivo and in vitro. For example, the diffusion of green fluorescent protein (GFP) in E. coli is ~10-fold slower than in dilute conditions. In this study, we performed Brownian dynamics (BD) simulations of rigid macromolecules in a crowded environment mimicking the cytosol of E. coli to study the motions of macromolecules. The simulation systems contained 35 70S ribosomes, 750 glycolytic enzymes, 75 GFPs, and 392 tRNAs in a 100 nm × 100 nm × 100 nm simulation box, where the macromolecules were represented by rigid-objects of one bead per amino acid or four beads per nucleotide models. Diffusion tensors of these molecules in dilute solutions were estimated by using a hydrodynamic theory to take into account the diffusion anisotropy of arbitrary shaped objects in the BD simulations. BD simulations of the system where each macromolecule is represented by its Stokes radius were also performed for comparison. Excluded volume effects greatly reduce the mobility of molecules in crowded environments for both molecular-shaped and equivalent sphere systems. Additionally, there were no significant differences in the reduction of diffusivity over the entire range of molecular size between two systems. However, the reduction in diffusion of GFP in these systems was still 4-5 times larger than for the in vivo experiment. We will discuss other plausible factors that might cause the large reduction in diffusion in vivo.