Carlos Floyd, UMD Biophysics Student
Hosted by Sergei Sukharev
Title: Exploring Mechanisms of Cytoskeletal Entropy Production Through Models and Simulations
Time: 4:00PM - 5:00PM
Date: Monday, September 9, 2019
Abstract
The actin-based cytoskeleton provides the cell with a means to transmit mechanical forces to its environment and within its body, allowing the cell to perform important physiological processes. During these processes, the chemical energy of ATP molecules is transduced into mechanical work, chiefly through the directed polymerization of actin filaments and the action of molecular motors such as myosin. A quantitative understanding of how the thermodynamic efficiency of these processes depends on the state of the cytoskeleton would allow for improved measurements of cellular work production, as well as shed light on theories from the field of active matter systems. To address this need, we rely on both analytical modeling and computational simulations of cytoskeletal structures, and we develop new methods to directly estimate entropy production in these frameworks. In the modeling, we treat the concentrations of actin monomers bound to nucleotides in several hydrolysis states using a mean-field description. With this we illustrate counter-intuitive dependencies of chemical energy consumption via filament aging on the concentrations of actin monomers and filaments. In the simulations, we extend the MEDYAN software package, which unites polymer mechanics with stochastic reaction-diffusion algorithms, to allow for calculations of chemical energy consumption and of mechanical stresses. We combine these calculations with metrics describing salient features of the system state to uncover new insights into what governs the efficiency of the cytoskeletal machinery.
William Bentley, University of Maryland College Park
Hosted by Sergei Sukharev
Title: Communicating with and controlling biology via biofabrication, synthetic biology, and microelectronics
Time: 4:00PM - 5:00PM
Date: Monday, September 16, 2019
Abstract
We are developing tools of “biofabrication” that enable facile assembly of biological components within devices, including microelectronic devices, that preserve their native biological function. By recognizing that biological redox active molecules are a biological equivalent of an electron-carrying wire, we have developed biological surrogates for electronic devices, including a biological redox capacitor that enable bi-directional “electron” flow. We have also turned to synthetic biology to provide a means to sample, interpret and report on biological information contained in molecular communications circuitry. To do this, we have participated in the discovery of bacterial quorum sensing and have “rewired” its regulatory components so as to enable eavesdropping on bacterial crosstalk. Finally, we have developed synthetic genetic circuits that enable electronic actuation of gene expression. That is, using simple reconstructions, one can apply voltage on an electrode and directly actuate genetic responses and associated phenotypes. This presentation will introduce the concepts of molecular communication that are enabled by integrating relatively simple concepts in synthetic biology with biofabrication. Our presentation will show how engineered cells represent a versatile means for mediating the molecular “signatures” commonly found in complex environments, or in other words, they are conveyors of molecular communication. These efforts comprise part of the Robert E. Fischell Institute, a new Institute meant to catalyze research and foster translation into clinical practice. The talk will also address the translational ecosystem at Maryland.
Veronica Ciocanel, Ohio State University
Hosted by Arpita Upadhyaya and Garegin Papoian
Title: Topological Data Analysis for Ring Channels in Intracellular Transport
Time: 4:00PM - 5:00PM
Date: Monday, September 30, 2019
Abstract
Contractile rings are cellular structures made of actin filaments that are important in development, wound healing, and cell division. In the reproductive system of the worm C. elegans, ring channels allow nutrient exchange between developing egg cells and the worm and are regulated by forces exerted by myosin motor proteins. In this talk, I will present an agent-based modeling and data analysis framework for the interactions between actin filaments and myosin motor proteins inside cells. This approach may provide key insights for the mechanistic differences between two motors that are believed to maintain the rings at a constant diameter. In particular, we propose tools from topological data analysis to understand time-series data of filamentous network interactions. Our proposed methods clearly reveal the impact of certain parameters on significant topological circle formation, thus giving insight into ring channel formation and maintenance.
John Tsang, National Institutes of Health (NIAID)
Hosted by Sergei Sukharev
Title: Do differences make a difference: human immune responsiveness and single-cell variations
Time: 4:00PM - 5:00PM
Date: Monday, October 7, 2019
Abstract
My lab works on developing and applying systems biology approaches— combining computation, modeling and experiments—to study the immune system at both the organismal and cellular levels. Heterogeneity—from cell-to-cell variations to differences among human individuals—is a hallmark of the immune system. I will highlight efforts in the lab for studying and utilizing such heterogeneities, including assessing condition-dependent information propagation in gene networks and studying the function of cell-to-cell variation of immune cell populations in humans, and recent efforts in simultaneously assessing proteins and transcriptome in single cells to study vaccination responses in the human population. A recurrent challenge we face is the development of predictive quantitative models because most molecular and cellular parameters have unknown values and realistic models are analytically intractable. Towards addressing these challenges, here I will also highlight a general framework we developed that combines mechanistic simulation of reaction systems and machine learning of the simulation data to generate computationally efficient predictive models and interpretable parameter-phenotype maps.
Valerie Daggett, University of Washington Seattle
Hosted by Kwaku Dayie
Title: Dynameomics: From Simulation of All Protein Folds to the Design of Amyloid Inhibitors and Diagnostics
Time: 4:00PM - 5:00PM
Date: Monday, October 21, 2019
Abstract
We have been involved in the development and use of realistic computer simulations of proteins to characterize the conformational changes associated with amyloid formation. In so doing we discovered a novel structure adopted by amyloidogenic proteins, but not ‘normal’ proteins, and we proposed that it defines the toxic soluble oligomers formed en route to the nontoxic mature fibrils. As such, this structure, which we call α-sheet, represents a new target for amyloid therapeutics and diagnostics. We have designed, synthesized, and tested compounds to be complementary to this ‘toxic’ structure and they inhibit amyloid formation of Aβ (Alzheimer’s Disease), transthyretin (systemic amyloid disease and heart disease), and amylin (type 2 diabetes), as well as several biofilmforming bacteria, by specifically binding the toxic oligomers, which in turn neutralizes the toxic species. These α-sheet compounds represent a novel platform for attacking these diseases and the hope of disease-modifying treatments and early diagnosis.
Ashok Prasad, Colorado State University
Hosted by Arpita Upadhyaya
Title:Development of Synthetic Switches in Plants
Time: 4:00PM - 5:00PM
Date: Monday, October 28, 2019
Abstract
Synthetic biology is the engineering of biologically based or inspired systems that display functions that do not exist in nature. Though the genetic engineering techniques it is based on have a longer history, synthetic biology is often said to have taken off when the first synthetic gene regulatory systems, a switch and an oscillator, were developed in e. coli and reported in 2000. Despite a long history of plant genetic engineering, the complexity of plant biology appears to have prevented the development of synthetic gene circuits in plants. However plant synthetic biology is of great interest since it can potentially lead to sustainable green technologies for human needs. In a collaborative project with a plant biologist we have developed the first ever synthetic genetic toggle switch in a plant. A key step in the rational design of synthetic networks is the quantitative characterization of components to enable predictive modeling. This poses special difficulties for plants, since stably transforming plants is time consuming. We developed an experimental system for rapid quantitative measurements of synthetically designed repressors using plant protoplasts but found that protoplast assays show significant experimental variability that leads to incorrect quantitative results. We developed a mathematical model that was successful in normalizing the data to make quantitative comparisons between different inducible repressors, and approximately predict quantitative properties of synthetic circuits in stably transformed plants. We tested hundreds of repressible promoters, and carried out a statistical analysis of the quantitative data to uncover design principles for building synthetic inducible repressors in plants (Nature Methods, v13, pp94–100, (2016)). Based on this previous work we predicted promoter-repressor pairs that could work together as a genetic toggle switch. Two different switches were constructed, plants stably transformed and then tested using a luciferase reporter. Quantitative analysis of the results confirms that one of them is a bistable genetic toggle switch, the first ever in a plant. Though challenges of achieving desirable design parameters and predictability remain, our work demonstrates that synthetic circuits that function in a predictable manner can be developed even for complex organisms that undergo sexual reproduction and go through several developmental stages.
Daniel Zuckerman, Oregon Health and Science University
Hosted by Pratyush Tiwary
Title: Simple ingredients, remarkable outcomes - Molecular machines and the secrets of life
Time: 4:00PM - 5:00PM
Date: Monday, November 4, 2019
Abstract
Biomolecules are governed by the laws of physics and chemistry, limiting them to four basic processes - binding, conformation change, catalysis, and diffusion. Remarkably, these basic processes can be coupled to generate all of cellular behavior. Prime exemplars are molecular machines, which can transport molecules against gradients, provide locomotion, and most remarkably of all, perform templated biosynthesis with error correction, as in protein translation by the ribosome. Although semi-quantitative models have been developed for many machines, both experiments and theory suggest these often are over-simplified. We therefore have attempted to apply fundamentals of biophysics to the task of systematic and automated model construction, an approach with potential to uncover hidden features of biomachine function.
Brian Weitzner, Lyell Immunopharma in Seattle
Hosted by Gregg Duncan
Title: Designing proteins for function
Time: 4:00PM - 5:00PM
Date: Monday, November 18, 2019
Abstract
Protein engineering has historically proceeded by identifying a naturally occurring protein that performs some or all of the desired functions, and then varying the amino-acid sequence either randomly or rationally in order to optimize it for the task at hand. This approach has limitations that are exposed when attempting to develop a protein to perform a novel function. Moreover, engineering proteins in this manner carries forward the complete evolutionary history of the starting protein. As protein-based technologies become increasingly desirable, we need a way to develop purpose-built proteins specifically for the task at hand. In order to achieve this, we must develop a deep understanding of the sequence–structure and structure–function relationships. We use an energetic model that integrates physics-based and statistical terms with a multi-start Monte Carlo simulated annealing sampling strategy implemented in the ROSETTA molecular modeling software to explore sequence space to generate sequences to fold into a desired conformation. In this talk, I will share two stories of de novo protein design: (1) designing protein mimetic that recapitulate the binding sites of natural cytokines that are otherwise unrelated in topology or amino acid sequence; and (2) a new method to generate active site geometries fully-connected by hydrogen bonds starting from a ChemDraw-like 2D representation of the transition state with hydrogen-bond donors, acceptors, and covalent interaction sites indicated to enable the design of novel enzymes.
Rafael Bruschweiler, Ohio State University
Hosted by Kwaku Dayie
Title: Observing Functional Protein Motions on Unchartered Timescales by NMR and Computer Simulations
Time: 4:00PM - 5:00PM
Date: Monday, December 9, 2019
Abstract
Multidimensional NMR relaxation experiments have played a pivotal role for the characterization of structural dynamics of many different proteins and their critical role in protein function. However, for nuclear spin physics reasons the observation of motions on timescales ranging from tens of nanoseconds to microseconds have remained elusive. I will introduce a novel approach that opens up this timescale window by the use of silica nanoparticles that transiently interact with the proteins of interest in solution. I will demonstrate how nanoparticle-assisted spin relaxation is able to uncover novel types of protein motions that were previously unobservable and how such motions can be validated using molecular dynamics (MD) simulations.