Series
Distinguished Lecture Series in Systems Biology

Series Type
Event Series
Description
Associated Organization(s)
Associated Organization(s)
Organizational Unit
Organizational Unit
School of Biological Sciences
School established in 2016 with the merger of the Schools of Applied Physiology and Biology

Publication Search Results

Now showing 1 - 10 of 34
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    Drug Discovery Accelerated by Computational Methods
    (Georgia Institute of Technology, 2013-04-30) Jorgensen, William L.
    Drug discovery is being pursued through computer-aided design, synthesis, biological assaying, and crystallography. Lead identification features de novo design with the ligand growing program BOMB or docking of commercial compound libraries. The cheminformatics program QikProp is applied to filter candidate molecules to ensure that they have drug-like properties. The focus of this lecture will be optimization of the resultant leads to yield potent inhibitors. Specifically, Monte Carlo/free-energy perturbation simulations are executed to identify the most promising choices for substituents on rings, heterocycles, and linking groups. The designed compounds are then synthesized and assayed. Successful application has been achieved for HIV reverse transcriptase, FGFR1 kinase, and human and Plasmodium falciparum macrophage migration inhibitory factor (MIF); micromolar leads have been rapidly advanced to low nanomolar or picomolar inhibitors.
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    Mapping Protein Folding on Organismal Fitness One Mutation at a Time
    (Georgia Institute of Technology, 2013-03-12) Shakhnovich, Eugene
    In this presentation I will describe our efforts at understanding how molecular properties of proteins determine fitness landscape of populations of carrier organisms. Recent multi-scale evolutionary models, which assume certain relationship between organismal fitness and stability of their proteins, have been successful in predicting such biological phenomena as lethal mutagenesis (six mutations per genome per generation), distributions of protein stabilities (‘’marginal’’ protein stability being a consequence of a mutation-selection balance), correlation between evolutionary rates and abundances. However, many of the underlying assumptions of these models have not been tested experimentally. Our recent efforts aim to close this gap. We explore fitness landscape of E.coli through controlled rational mutational genomic perturbations of expression level and stability of essential protein Dihydrofolate Reductase (DHFR). To that end we created transgenic E.coli, which carry specified mutations in the folA gene encoding DHFR and also placed the folA gene under an IPTG controllable promoter, making it possible to change the intracellular abundance of DHFR in a wide range. Using competition essays, we measured how biological fitness depends on Biophysical properties of DHFR such as its abundance in the cytoplasm, stability of its native state and folding intermediate, and catalytic activity. Mutant DHFR proteins in a few strains aggregated rendering them nonviable but the majority exhibited fitness higher than wild type at a growth temperature of 42oC. We found that mutational destabilization of DHFR proteins in E. coli is counterbalanced by soluble oligomerization that restores their structural stability and protects from aggregation. Further, we found that protein homeostasis plays a defining role in sculpting fitness effect of mutations. In particular, overexpression of GroEL as well as deletion of one of the proteases, Lon, resulted in complete recovery of fitness of unviable strains. Further study, including in vitro essays of ANS binding showed that GroEL and Lon compete for folding intermediate of DHFR and their relative concentrations determines the outcome. We developed a computational model to analyze this competition, which lead us to the conclusion that our observations cannot be reconciled with GroEL role as just caging device to protect DHFR mutants from aggregation and proteolysis. Rather, it must play an active role converting intermediate to folded molecules.
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    Histone Variants, Nucleosome Dynamics and Epigenetics
    (Georgia Institute of Technology, 2013-02-12) Henikoff, Steven
    The Henikoff Lab's recent studies have aimed to understand the elusive relationship between chromatin and epigenetic inheritance. In large part, their focus has been on the universal set of histone variants that replace canonical histones independent of replication.
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    Structural Basis for Iron Piracy by Pathogenic Neisseria
    (Georgia Institute of Technology, 2012-10-16) Buchanan, Susan
    Neisseria 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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    Development and Evolution of Vertebrate Development and Evolution of Vertebrate
    (Georgia Institute of Technology, 2012-04-24) Tabin, Clifford
    Dr. 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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    The ESCRT pathway in HIV Budding and Cell Division
    (Georgia Institute of Technology, 2012-01-31) Sundquist, Wesley
    The 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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    New approaches to studying the growth and size regulation of mammalian cells
    (Georgia Institute of Technology, 2012-01-24) Kirschner, Marc
    The 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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    New Biology from Natural Metamorphosis of a Conventional Class of Enzymes
    (Georgia Institute of Technology, 2011-11-15) Schimmel, Paul
    A 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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    Protein Folding Inside Cells and Other Crowded Environments
    (Georgia Institute of Technology, 2011-11-08) Gruebele, Martin
    Computer 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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    Cheminformatic 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.