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ItemStructural Basis for Iron Piracy by Pathogenic Neisseria(Georgia Institute of Technology, 2012-10-16) Buchanan, SusanNeisseria are obligate human pathogens causing bacterial meningitis, septicemia, and gonorrhea. Neisseria require iron for survival and can extract it directly from human transferrin for transport across the outer membrane. The transport system consists of TbpA, an integral outer membrane protein, and TbpB, a co-receptor attached to the cell surface; both proteins are potentially important vaccine and therapeutic targets. Two key questions driving Neisseria research are: 1) how human transferrin is specifically targeted, and 2) how the bacteria liberate iron from transferrin at neutral pH. To address them, we solved crystal structures of the TbpA-transferrin complex and of the corresponding co-receptor TbpB. We characterized the TbpB-transferrin complex by small angle X-ray scattering and the TbpA-TbpB-transferrin complex by electron microscopy. Collectively, our studies provide a rational basis for the specificity of TbpA for human transferrin, show how TbpA promotes iron release from transferrin, and elucidate how TbpB facilitates this process.
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ItemKrylov subspace methods for computing hydrodynamic interactions in Brownian dynamics simulations(Georgia Institute of Technology, 2012-08) Ando, Tadashi ; Chow, Edmond ; Saad, Yousef ; Skolnick, JeffreyHydrodynamic interactions play an important role in the dynamics of macromolecules. The most common way to take into account hydrodynamic effects in molecular simulations is in the context of a Brownian dynamics simulation. However, the calculation of correlated Brownian noise vectors in these simulations is computationally very demanding and alternative methods are desirable. This paper studies methods based on Krylov subspaces for computing Brownian noise vectors. These methods are related to Chebyshev polynomial approximations, but do not require eigenvalue estimates. We show that only low accuracy is required in the Brownian noise vectors to accurately compute values of dynamic and static properties of polymer and monodisperse suspension models. With this level of accuracy, the computational time of Krylov subspace methods scales very nearly as O(N²) for the number of particles N up to 10 000, which was the limit tested. The performance of the Krylov subspace methods, especially the “block” version, is slightly better than that of the Chebyshev method, even without taking into account the additional cost of eigenvalue estimates required by the latter. Furthermore, at N = 10 000, the Krylov subspace method is 13 times faster than the exact Cholesky method. Thus, Krylov subspace methods are recommended for performing largescale Brownian dynamics simulations with hydrodynamic interactions.
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ItemDevelopment and Evolution of Vertebrate Development and Evolution of Vertebrate(Georgia Institute of Technology, 2012-04-24) Tabin, CliffordDr. Tabin's laboratory studies the genetic basis by which form and structure are regulated during vertebrate development. They combine classical methods of experimental embryology with modern molecular and genetic techniques for regulating gene expression during embryogenesis.
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ItemThe ESCRT pathway in HIV Budding and Cell Division(Georgia Institute of Technology, 2012-01-31) Sundquist, WesleyThe Endosomal Sorting Complexes Required for Transport (ESCRT) pathway mediates intraluminal endosomal vesicle formation, budding of HIV-1 and other enveloped viruses, and the final abscission step of cytokinesis in mammals and archaea. I will review our current understanding of the roles of different EXCRT factors in HIV budding, and then discuss our recent findings that in addition to their roles in abscission, EXCRT factors are also required for several key steps in mitosis, including creation of the bipolar spindle and proper pairing and segregation of sister chromatids. Our studies indicate that the EXCRT pathway functions at both centrosomes and centromeres during mitosis, and then at midbodies during abscission, thereby helping to ensure ordered progression through the different stages of cell division.
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ItemNew approaches to studying the growth and size regulation of mammalian cells(Georgia Institute of Technology, 2012-01-24) Kirschner, MarcThe study of cell growth has been limited primarily by the lack of accurate enough means of measuring the growth of cells as they traverse the cell cycle. There are several theoretical models of growth that have been impossible to evaluate because the methods for measuring growth have been too inaccurate to distinguish among them. In particular, if cells grow proportional to their mass, which of course doubles each cell cycle, then it is likely that the variation in cell size in a population would increase without limit. This is simply because cell division is rarely completely symmetric, producing smaller cells that would grow slower and larger cells that would grow faster. On the other hand, if cells added equal mass per unit time this undesirable outcome could be avoided. There are ideas that size control may not exist but simply be driven by exogenous and independent controls of cell cycle and growth, size being simply a resultant of these explicity controls. Yet the very strict size regulation of different cell types, suggests that cell size is an evolutionary optimum for different functions and hence, cells should have a homeostatic mechanism for maintaining cell size. There are other speculations that cells grow to a defined size and then divide, making cell division a slave to cell growth. The opposite is also possible that passage through the cell cycle feeds back on cell growth. To approach these questions we have developed two new analytical techniques of exquisite sensitivity. In collaboration with Scott Manalis at MIT, we used his suspended microchannel resonator to measure cell mass to 0.01% and to do that for as many as 8 generations without causing any known harm to the cells. This technique pointed to a sharp transition of growth at the G1/S transition. It also shows that a size threshold does not exist in a mammalian cell line but instead there is convergence of cell growth rates at G1/S. Another technique which Ran Kafri, a postdoc in my lab and Galit Lahav's lab developed used a static population based approach to derive very sensitive kinetic features based on the ergodic assumption of steady state growth. This method opens up many new measurements not possible in growing individual cells; here temporal resolution and sensitivity is increased markedly as cell numbers exceed a million. This method also described a period at the feedback on growth rate at the G1/S transition. These new measurements suggest that there is a sizing mechanism in mammalian cells that reduces variation in the cell cycle by affecting growth rate and size dependence of growth rate. Such a mechanism is liked to be tuned and respond differently in different cell types and under different conditions.
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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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