MULTISCALE MODELS FOR SYNTHETIC BIOLOGY
Yiannis Kaznessis, Associate Professor
University Of Minnesota Twin Cities, 450 Mcnamara Alumni Center, Minneapolis, Mn 55455-2070
Grant 1R01GM086865-01A2 from National Institute Of General Medical Sciences
Abstract: Humans can now construct and piece together DNA sequences in order to design new biological systems and organisms. We can do this more quickly and less expensively than ever. Applications abound for our synthetic biological constructs, from sensors of biochemical and chemical weapons, to devices that will remove environmental pollutants, to gene therapies. Synthetic biology is the discipline that focuses on the construction of these novel biological systems. It has all the characteristic features of an engineering discipline applying technical and scientific knowledge to design and implement devices, systems, and processes that safely realize a desired objective. Mathematical modeling has always been an important component of engineering disciplines. It can play an important role in synthetic biology the same way modeling helps in aircraft or architecture design models and computer simulations can quickly provide a clear picture of how different components influence the behavior of the whole, reaching objectives quickly. The proposed activities will result in modeling tools that will help scientists and engineers to construct complex synthetic biological systems. These tools will be standardized, so that they are applicable to any synthetic biological system. The activities will also produce novel synthetic gene regulatory networks that can find applications in pharmaceutical production and gene therapies. We will develop sophisticated mathematical models of synthetic biological systems that connect the targeted biological phenotype (what we want the synthetic biological system to do) to the DNA sequence (that we need to physically construct to realize the synthetic biological system). We will conduct simulations of many alternate designs to decide on the optimum set of molecular components, before we go into the wet laboratory. We will then construct these designs in E. coli and optimize them for performance. We propose to work with synthetic tetracycline inducible networks because they have significant biomedical applications, mainly as gene therapy expression vectors. Tetracycline is a small antibiotic molecule that can safely turn on the production of any protein, when this protein is expressed under the control of a tetracycline-responsive DNA promoter. We will model, design, build and test these promoters to determine how to best control protein expression with tetracycline induction
Keywords: Address; Aircraft; Algorithms; Antibiotic Agents; Antibiotic Drugs; Antibiotics; Architecture; Arm; Artificial Genes; Automation; Behavior; Bio-Informatics; Biochemical; Biochemical Reaction; Bioinformatics; Biological; Biosensor; Biotechnology, Genetic Engineering; Budgets; Characteristics; Chemical Weapons; Cloning; Complex; Computer Assisted; Computer Programs; Computer Simulation; Computer Software Tools; Computer software; Computerized Models; DNA; DNA Molecular Biology; DNA Sequence; Deoxyribonucleic Acid; Devices; Discipline; Drug Formulations; Drugs; E coli; Engineering; Engineering / Architecture; Engineerings; Environmental Pollutants; Enzymatic Reaction; Equilibrium; Escherichia coli; Feedback; Formulation; Formulations, Drug; Gene Transcription; Gene Transfer Clinical; Gene Transfer Procedure; Gene-Tx; Genes; Genes, Regulator; Genes, Reporter; Genetic Engineering; Genetic Intervention; Genetic Transcription; Graphical interface; Human; Human, General; Humulin R; Insulin; Insulin (ox), 8A-L-threonine-10A-L-isoleucine-30B-L-threonine-; Insulin, Regular; Intervention, Genetic; Journals; Kinetic; Kinetics; Knowledge; Laboratories; Logic; Magazine; Man (Taxonomy); Man, Modern; Math Models; Mathematical Model Simulation; Mathematical Models and Simulations; Medication; Methods; Miscellaneous Antibiotic; Modeling; Models, Computer; Molecular; Molecular Biology; Molecular Biology, Gene Therapy; Molecular Biology, Genetic Engineering; Noise; Novolin R; Operon; Organism; Performance; Pharmaceutic Preparations; Pharmaceutical Agent; Pharmaceutical Preparations; Pharmaceuticals; Pharmacologic Substance; Pharmacological Substance; Phenotype; Physiologic; Physiological; Play; Process; Production; Programs (PT); Programs [Publication Type]; Promoter; Promoters (Genetics); Promotor; Promotor (Genetics); Proteins; Publishing; RNA Expression; Reaction; Recombinant DNA Technology; Regulation; Regulator Genes; Reporter Genes; Research; Rest; Role; Scientist; Simulate; Simulation, Computer based; Software; Software Tools; Synthetic Genes; System; System, LOINC Axis 4; Testing; Tetracycline Antibiotic; Tetracyclines; Therapy, DNA; TimeLine; Tools, Software; Transcription; Transcription, Genetic; Transcriptional Regulatory Elements; Translations; Upper arm; Work; balance; balance function; base; behavior influence; behavioral influence; biological systems; computational modeling; computational models; computational simulation; computer aided; computer based models; computer program/software; computerized modeling; computerized simulation; design; design and construction; designing; drug/agent; experiment; experimental research; experimental study; expression vector; feeding; gene product; gene therapy; genetic therapy; graduate student; graphic user interface; graphical user interface; in silico; living system; mathematical model; mathematical modeling; model design; multi-scale modeling; multiscale modeling; novel; programs; protein expression; public health relevance; regulatory gene; research study; sensor; sensor (biological); simulation; social role; supercomputer; synthetic DNA; synthetic biology; synthetic construct; theories; therapeutic protein; tool; trans acting element; transcription factor; virtual simulation; wiki
Relevance: Imagine trying to engineer a biological sensor that senses a small drug molecule and responds by turning on the expression of a therapeutic protein, say insulin. Now imagine having a software tool that can assist in engineering the sensor quickly. The proposed activities will result in modeling tools for computer-aided construction of complex synthetic biological systems. The activities will also produce novel synthetic gene regulatory networks with applications in pharmaceutical production and gene therapies. 25-word Summary/Public Health Relevance Statement The proposed activities will result in publicly available mathematical tools, useful in computeraided construction of synthetic biological systems, which find applications in gene therapies
Project start date: 2009-09-30
Project end date: 2011-08-31
Budget start date: 30-SEP-2009
Budget end date: 31-AUG-2010
PFA/PA: PA-07-070
1R01GM086865-01A2 (2009): $249550
Sponsored Links Excellgen http://Excellgen.com
Grants awarded to Yiannis Kaznessis
COMPUTATIONAL MODELING AND DESIGN OF ANTIMICROBIAL PEPTIDES
Yiannis Kaznessis
Department/ Educational Institution Type:
Grant 5R01GM070989-05 from National Institute Of General Medical Sciences
Abstract: We propose the development of computational tools that promote the progress of antimicrobial peptide engineering. Drug-resistant pathogens are becoming a significant public health concern. The prolific use of antibiotics in the last few decades inevitably increased the bacterial species with resistance. Antimicrobial peptides (AMPs), recognized as potent components of eukaryotic innate immune response mechanisms, appear to be promising therapeutic anti-pathogen agents. A wide array of experiments suggests a complex interplay between the bacterial cell envelope components and the peptides. However, how exactly AMPs modulate membrane structure remains largely unclear. We leverage the high resolution, atomic level picture of molecular dynamics simulations, to understand the interactions of AMPs with bacterial and mammalian membranes. We also develop data mining algorithms that identify recurring sequence and structural patterns in known, naturally occurring AMPs. Importantly, active collaborations with leading research groups in the areas of antimicrobial peptides and peptide/membrane interactions provide the necessary feedback mechanism for validation and refinement of computational results. The three specific aims of this project are 1. Quantify the interactions between AMPs and mammalian, bacterial and viral model membranes using high productivity computer simulations. 2. Recognize the sequence/structural elements that are responsible for cathelicidin and minidefensin antimicrobial activity 3. Establish a process of feedback mechanisms between experiments, computer models and new experimental design in order to promote rational peptide engineering. Experimentally investigate novel peptides based on model-driven design rules
Keywords: Algorithms; aminoacid sequence of peptide; aminoacid sequence of protein; anti-microbial; Antibiotic Agents; Antibiotic Drugs; Antibiotics; antimicrobial; antimicrobial peptide; Antiviral Agents; Antiviral Drugs; Antivirals; Area; balance; balance function; base; Binding; Binding (Molecular Function); Bio-Informatics; Bioinformatics; Biological; Biological Models; biomedical scientist; Blood - brain barrier anatomy; Blood-Brain Barrier; Categories; cathelicidin; cell envelope; Cell membrane; Cell Wall; Chemical Engineering; chemical informatics; cheminformatics; Classification; Classification Scheme; Collaborations; Complex; computational methodology; computational methods; computational modeling; computational models; Computational Science; computational simulation; computational tools; computer based models; computer methods; computer science; Computer Simulation; computerized modeling; Computerized Models; computerized simulation; computerized tools; Computing Methodologies; conformation; conformational state; Cytoplasmic Membrane; data mining; datamining; design; designing; Development; digital; Doctor of Philosophy; Drug resistance; drug resistant; Electrostatics; Elements; Engineering; Engineerings; Environment; Equilibrium; Exhibits; experience; experiment; Experimental Designs; experimental research; experimental study; Family; Feedback; Foundations; graduate student; heavy metal lead; heavy metal Pb; Hemato-Encephalic Barrier; Hemolysis; host response; Hydrocarbons; Hydrogen Bonding; Hydrophobic Interactions; Hydrophobicity; Immune response; immunoresponse; improved; in silico; In Vitro; in vivo; Institutes; Investigators; Knowledge; knowledge base; Laboratories; Lead; Light; lipid bilayer membrane; Lipid Bilayers; Lung-Surfactant Proteins; Mammalian Cell; Mathematical Model Simulation; Mathematical Models and Simulations; Measurement; Mechanics; Mediating; Membrane; membrane model; membrane structure; Methods; Micelles; Minnesota; Miscellaneous Antibiotic; model design; Model System; Modeling; Models, Biologic; Models, Computer; Molecular; Molecular Configuration; Molecular Conformation; molecular dynamics; Molecular Dynamics Simulation; Molecular Interaction; molecular mechanics; Molecular Stereochemistry; novel; Paper; pathogen; Pattern; Pattern Recognition; Pattern Recognition/Display/Analysis; Pb element; peptide sequence; Peptide Synthesis; Peptides; Ph.D.; Pharmaceutical Agent; Pharmaceuticals; Pharmacologic Substance; Pharmacological Substance; PhD; Phosphatides; Phospholipids; Photoradiation; Physics; Plasma Membrane; plasmalemma; post-doc; post-doctoral; Postdoc; Postdoctoral Fellow; Process; Productivity; programs; Programs (PT); Programs [Publication Type]; protein aminoacid sequence; Protocol; Protocols documentation; PSFAP; Public Health; public health medicine (field); Publications; Pulmonary Surfactant-Associated Proteins; Pulmonary Surfactant-Associated Proteolipid; Qualifying; Research; Research Associate; Research Personnel; Research Resources; research study; Researchers; Resistance; resistance to Drug; resistant; resistant to Drug; Resolution; Resources; Scheme; Science; Scientific Publication; Scientist; simulation; Simulation, Computer based; skills; Solid; sound; Sound; Sound - physical agent; Specificity; Speed; Speed (motion); Structure; success; Supercomputing; System; System, LOINC Axis 4; Systematics; Technology; Testing; Therapeutic; tool; Toxic effect; Toxicities; Training; Trypsin Inhibitors; Validation; Viral; virtual simulation; Work
Project start date: 2005-08-01
Project end date: 2011-07-31
Budget start date: 1-AUG-2009
Budget end date: 31-JUL-2011
PFA/PA: PAR-03-106
5R01GM070989-05 (2009): $217767
5R01GM070989-04 (2008): $217821
Computational Modeling /Design Of Antimicrobial Peptides
Yiannis Kaznessis, Associate Professor
University Of Minnesota Twin Cities 450 Mcnamara Alumni Center Minneapolis, Mn 554552070
Grant 5R01GM070989-03 from National Institute Of General Medical Sciences IRG: ZRG1
Abstract: We propose the development of computational tools that promote the progress of antimicrobial peptide engineering. Drug-resistant pathogens are becoming a significant public health concern. The prolific use of antibiotics in the last few decades inevitably increased the bacterial species with resistance. Antimicrobial peptides (AMPs), recognized as potent components of eukaryotic innate immune response mechanisms, appear to be promising therapeutic anti-pathogen agents. A wide array of experiments suggests a complex interplay between the bacterial cell envelope components and the peptides. However, how exactly AMPs modulate membrane structure remains largely unclear. We leverage the high resolution, atomic level picture of molecular dynamics simulations, to understand the interactions of AMPs with bacterial and mammalian membranes. We also develop data mining algorithms that identify recurring sequence and structural patterns in known, naturally occurring AMPs. Importantly, active collaborations with leading research groups in the areas of antimicrobial peptides and peptide/membrane interactions provide the necessary feedback mechanism for validation and refinement of computational results. The three specific aims of this project are 1. Quantify the interactions between AMPs and mammalian, bacterial and viral model membranes using high productivity computer simulations. 2. Recognize the sequence/structural elements that are responsible for cathelicidin and minidefensin antimicrobial activity 3. Establish a process of feedback mechanisms between experiments, computer models and new experimental design in order to promote rational peptide engineering. Experimentally investigate novel peptides based on model-driven design rules.
Keywords: antiinfective agent, computational biology, computer simulation, drug design /synthesis /production, intermolecular interaction, membrane activity, molecular dynamics, protein engineering, antibacterial agent, antiviral agent, defensin, experimental design, host organism interaction, immune response, membrane model, membrane permeability, membrane structure, protein structure function, bioinformatics, biotechnology, enzyme linked immunosorbent assay, human tissue, proteomics, surface plasmon resonance
Project start date: 2005-08-01
Project end date: 2010-07-31
5R01GM070989-03 (2007): $214072
5R01GM070989-02 (2006): $220518
1R01GM070989-01A2 (2005): $236124
BIOMOLECULAR INTERACTION AND GENE NETWORK SIMULATIONS
Yiannis Kaznessis, Associate Professor
Carnegie-mellon University, 5000 Forbes Ave, Pittsburgh, Pa 15213
Abstract: This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. a) Computer Simulations of Antimicrobial Peptides. Disease causing microbes are becoming resistant to common antibiotics, and are thus emerging as a serious threat to public health. Researchers are being forced to look for novel antibiotic formulations to combat this menace. Optimism in antimicrobial peptides (AMPs) as substitutes of conventional antibiotics has been triggered by knowledge of their quick and strong antimicrobial action, as well as the non-specific membrane-mediated mechanism of AMP-induced cell death. However, the design of novel AMPs with attenuated host cell toxicity has been impeded by a lack of molecular-scale fundamental knowledge of AMP-membrane interaction events. In our work, we use all-atom molecular dynamics simulations of AMPs in membrane mimics to decipher which sequence and structure components of AMPs are responsible for activity and toxicity b) Synthetic Bioengineering of Gene Regulatory Networks The ambitious idea of engineering cells that will function as miniature factories has given rise to new fields of research, systems and synthetic biology. We have developed multi-scale, stochastic simulation methods that can guide rational engineering of synthetic networks. Our method approximates fast and continuously occurring reactions as a continuous Markov process, but maintains slow or discontinuously occurring reactions in its original form, which is a jump Markov process. Because these two processes are highly coupled, their solution must proceed simultaneously
Keywords: Antibiotic Agents; Antibiotic Drugs; Antibiotics; Attenuated; Biomedical Engineering; Biomedical Research; CRISP; Cell Death; Cells; Computer Retrieval of Information on Scientific Projects Database; Computer Simulation; Computerized Models; Coupled; Disease; Disorder; Drug Formulations; Engineering; Engineerings; Event; Formulation; Formulations, Drug; Funding; Genes, Regulator; Grant; High Performance Computing; Institution; Investigators; Knowledge; Markov Chains; Markov Process; Mathematical Model Simulation; Mathematical Models and Simulations; Mediating; Membrane; Methods; Microbe; Miscellaneous Antibiotic; Models, Computer; Molecular Dynamics Simulation; NIH; National Institutes of Health; National Institutes of Health (U.S.); Process; Public Health; Reaction; Regulator Genes; Research; Research Personnel; Research Resources; Researchers; Resistance; Resources; Simulation, Computer based; Solutions; Source; Structure; Toxic effect; Toxicities; Transcriptional Regulatory Elements; United States National Institutes of Health; Work; anti-microbial; antimicrobial; antimicrobial peptide; bioengineering; bioengineering/biomedical engineering; cell engineering; cellular engineering; combat; computational modeling; computational models; computational simulation; computer based models; computerized modeling; computerized simulation; design; designing; disease/disorder; gene interaction; in silico; membrane structure; molecular dynamics; molecular scale; necrocytosis; novel; optimism; postiive attitude; public health medicine (field); regulatory gene; resistant; simulation; synthetic biology; systems research; trans acting element; virtual simulation
Project start date: 2009-08-01
Project end date: 2010-07-31
Budget start date: 1-AUG-2009
Budget end date: 31-JUL-2010
5P41RR006009-19_6338 (2009): $771
MULTISCALE MODELS FOR SYNTHETIC BIOLOGY
Yiannis Kaznessis
University Of Minnesota Twin Cities, 450 Mcnamara Alumni Center, Minneapolis, Mn 55455-2070
Grant 5R01GM086865-02 from National Institute Of General Medical Sciences
Abstract: Humans can now construct and piece together DNA sequences in order to design new biological systems and organisms. We can do this more quickly and less expensively than ever. Applications abound for our synthetic biological constructs, from sensors of biochemical and chemical weapons, to devices that will remove environmental pollutants, to gene therapies. Synthetic biology is the discipline that focuses on the construction of these novel biological systems. It has all the characteristic features of an engineering discipline applying technical and scientific knowledge to design and implement devices, systems, and processes that safely realize a desired objective. Mathematical modeling has always been an important component of engineering disciplines. It can play an important role in synthetic biology the same way modeling helps in aircraft or architecture design models and computer simulations can quickly provide a clear picture of how different components influence the behavior of the whole, reaching objectives quickly. The proposed activities will result in modeling tools that will help scientists and engineers to construct complex synthetic biological systems. These tools will be standardized, so that they are applicable to any synthetic biological system. The activities will also produce novel synthetic gene regulatory networks that can find applications in pharmaceutical production and gene therapies. We will develop sophisticated mathematical models of synthetic biological systems that connect the targeted biological phenotype (what we want the synthetic biological system to do) to the DNA sequence (that we need to physically construct to realize the synthetic biological system). We will conduct simulations of many alternate designs to decide on the optimum set of molecular components, before we go into the wet laboratory. We will then construct these designs in E. coli and optimize them for performance. We propose to work with synthetic tetracycline inducible networks because they have significant biomedical applications, mainly as gene therapy expression vectors. Tetracycline is a small antibiotic molecule that can safely turn on the production of any protein, when this protein is expressed under the control of a tetracycline-responsive DNA promoter. We will model, design, build and test these promoters to determine how to best control protein expression with tetracycline induction
Keywords: Address; Algorithms; Arm; Artificial Genes; Automation; Behavior; Biochemical; Biochemical Reaction; Biologic Sciences; Biological; Biological Sciences; Biology; Biotechnology, Genetic Engineering; Chemical Weapons; Communities; Complex; Computer Programs; Computer Simulation; Computer software; Computer-Aided Design; Computer-Assisted Design; Computerized Models; Cytofluorometry, Flow; DNA Molecular Biology; DNA Sequence; Data; Development; Devices; Discipline; Drug Formulations; E coli; Engineering; Engineerings; Environmental Pollutants; Enzymatic Reaction; Equilibrium; Escherichia coli; Feedback; Flow Cytofluorometries; Flow Cytometry; Flow Microfluorimetry; Formulation; Formulations, Drug; Gene Expression; Gene Transcription; Gene Transfer Clinical; Gene Transfer Procedure; Gene-Tx; Genes; Genes, Regulator; Genetic Engineering; Genetic Intervention; Genetic Transcription; Graphical interface; Intervention, Genetic; Kinetic; Kinetics; Life Sciences; Logic; Math Models; Mathematical Model Simulation; Mathematical Models and Simulations; Mathematics; Methods; Microfluorometry, Flow; Modeling; Models, Computer; Molecular; Molecular Biology; Molecular Biology, Gene Therapy; Molecular Biology, Genetic Engineering; Noise; Operon; Organism; Personal Computers; Phenotype; Physiologic; Physiological; Play; Process; Promoter; Promoters (Genetics); Promotor; Promotor (Genetics); Publishing; RNA Expression; Reaction; Recombinant DNA Technology; Regulation; Regulator Genes; Reporter Genes; Role; Scientist; Simulate; Simulation, Computer based; Software; Synthetic Genes; System; System, LOINC Axis 4; Tetracycline Antibiotic; Tetracyclines; Therapy, DNA; Thermodynamic; Thermodynamics; Transcription; Transcription, Genetic; Transcriptional Regulatory Elements; Translations; Upper arm; Work; balance; balance function; base; behavior influence; behavioral influence; biological systems; computational modeling; computational models; computational simulation; computer based models; computer program/software; computerized modeling; computerized simulation; design; designing; detector; experiment; experimental research; experimental study; feeding; flow cytophotometry; gene therapy; genetic therapy; graphic user interface; graphical user interface; in silico; living system; mathematical model; mathematical modeling; multi-scale modeling; multiscale modeling; network models; novel; protein expression; regulatory gene; research study; simulation; social role; success; supercomputer; synthetic DNA; synthetic biology; synthetic construct; theories; tool; trans acting element; transcription factor; user-friendly; virtual simulation; wiki
Relevance: Narrative Synthetic biologists and engineers can now quickly construct and piece together non-naturally ocuring DNA sequences to design new, synthetic biological systems and organisms. Thus scientists are now afforded more precise control of biological systems and their functions than ever before. Applications abound, such as detectors for biochemical and chemical weapons, devices that will remove environmental pollutants, and gene therapies. Modeling tools can play an important role in synthetic biology the same way modeling helps in aeronautical or architectural design: simulations can quickly provide a clear picture of how different components influence the behavior of the whole. The proposed activities wil result in modeling tools that will help engineers to construct complex synthetic biological systems with new functions
Project start date: 2009-09-30
Project end date: 2011-08-31
Budget start date: 1-SEP-2010
Budget end date: 31-AUG-2011
PFA/PA: PA-07-070
5R01GM086865-02 (2010): $247072
Modeling And Design Of Antimicrobial Cathelicidins
Yiannis Kaznessis
Mellon Pitts Corporation (mpc Corp) Pittsburgh, Pa 152133890
Grant 5P41RR006009-150439 from National Center For Research Resources IRG: ZRG1
Keywords: antiinfective agent, biomedical resource, chemical model, drug design /synthesis /production, lipopolysaccharide
Project start date: 2004-08-01
Project end date: 2005-07-31