Tamar Schlick - US grants
Affiliations: | Program in Computational Biology | New York University, New York, NY, United States |
Area:
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The funding information displayed below comes from the NIH Research Portfolio Online Reporting Tools and the NSF Award Database.The grant data on this page is limited to grants awarded in the United States and is thus partial. It can nonetheless be used to understand how funding patterns influence mentorship networks and vice-versa, which has deep implications on how research is done.
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High-probability grants
According to our matching algorithm, Tamar Schlick is the likely recipient of the following grants.Years | Recipients | Code | Title / Keywords | Matching score |
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1987 — 1991 | Broyde, Suse [⬀] Overton, Michael (co-PI) [⬀] Peskin, Charles (co-PI) [⬀] Schlick, Tamar |
N/AActivity Code Description: No activity code was retrieved: click on the grant title for more information |
@ New York University The goal for the research proposed here is to develop mathematical tools for computing three-dimensional structures of large biological molecules. In particular, modeling and large- scale minimization techniques will be devised to predict the conformations of single and doublestranded RNA and DNA molecules. The computational tools involve semi-empirical potential energy minimization and molecular dynamics, executed on the Cray X-MP and aided by interactive computer graphics on the Evans and Sutherland PS-330. The plan is to work on the following four areas of program development: (1) Global optimization strategies; test the determination Tunneling method of Levy and Gomez and a variant of the stochastic Simulated Annealing: (2) Faster manipulation of the pairwise interactions in the energy function; investigate the new method recently proposed by Greengard and Rokhlin which could reduce the order O(N2) computational complexity for an N - particle system to order O(N): (3) Implementation of molecular dynamics: dynamics simulations will enable an examination of the dynamic trajectories of the structures obtained from minimization; and: (4) Incorporation of solvent and metalions into the molecular model; this will provide a more realistic potential field to represent the molecular forces influencing the RNA and DNA in its natural milieu. The developed computational tools will yield the ability to investigate some intriquing problems of three-dimensional molecular structures. These problems include the dependence of DNA conformation on the nucleic acid base sequence and the structure and the complex folding patterns of single-stranded RNA. The minimizations and dynamics results will be used to make 16 mm films and videotapes that will reveal the dynamic range of structures and permit us to relate conformational features with known biological functions. This proposal projects to develop mathematical tools, using state-of-the-art optimization algorithms, for examination of dynamics simulation of solvent and metal-ion interaction in the biologically important molecular RNA and DNA. The Program Director for Computational Science and Engineering recommends support in the sum of $69,370 for a period of one year. |
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1987 — 1991 | Schlick, Tamar | N/AActivity Code Description: No activity code was retrieved: click on the grant title for more information |
Mathematical Sciences Postdoctoral Research Fellowship @ Individual Award |
0.901 |
1990 — 1994 | Broyde, Suse (co-PI) [⬀] Overton, Michael (co-PI) [⬀] Peskin, Charles (co-PI) [⬀] Schlick, Tamar Greengard, Leslie (co-PI) [⬀] |
N/AActivity Code Description: No activity code was retrieved: click on the grant title for more information |
@ New York University Dr. Tamar Schlick is supported by a grant from the Theoretical and Computational Chemistry Program in the Chemistry Division, the Databases, Software Development and Computational Biology Program in the Division of Instrumentation and Resources, and the New Technologies Program in the Division of Advanced Scientific Computing to develop new computer algorithms for performing molecular mechanics and molecular dynamics calculations. These new algorithms will be used to predict nucleic acid and protein structures with the aid of supercomputers. In this research Schlick and coworkers will continue to address some of the fundamental computational and theoretical problems in the field of molecular modeling by: 1) devising more efficient nonlinear minimization techniques for complex large scale problems; 2) using larger time steps in molecular dynamics simulations; 3) including quantum-mechanical effects in molecular dynamics simulations; and 4) reducing the computation time for the pairwise nonbonded interactions. The algorithms which are developed will be used to study sequence-dependent folding pathways of closed circular DNA duplexes. The ultimate goal of this research is to explore the detailed folding pathways and important transitions in nucleic acids and proteins. |
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1993 — 1996 | Schlick, Tamar | N/AActivity Code Description: No activity code was retrieved: click on the grant title for more information |
@ New York University 9310295 Schlick The goal in this proposal is to extend this work further so that is can be applied routinely to protein and nucleic acids. We propose to develop and implement a new algorithm that combines implicit-integration and normal-mode techniques. The new algorithm will maintain the large time-step stability inherited in the implicit scheme, but also resolve the high-frequency components of the motion so that the activities of high-frequency modes can be retained. With parallel implementations on state-of-the-art machines, this will make possible simulations at time-steps of order 100 femtoseconds; the total simulation time will then approach the millisecond range. |
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1997 — 2000 | Schlick, Tamar | N/AActivity Code Description: No activity code was retrieved: click on the grant title for more information |
Postdoc: Brownian Dynamics of Dna Slithering @ New York University The PI's will develop and apply novel computational modeling techniques on high-performance computers to enhance our understanding of DNA on a global level, i.e., thousands of base pairs. Specifically, the PI's will describe the dynamical features of slithering in supercoiled DNA over microsecond to millisecond time frames. Slithering, which is thought to be important in recombination mechanisms, is a reptilian motion in which individual base pairs slide against each other in a "conveyor-belt" fashion. The PI's will extend a previously developed Langevin dynamics model of supercoiled DNA to incorporate hydrodynamic interactions. The DNA molecule will be represented by a B-spline model that smoothly transforms into a bead model. The singular value decomposition will be used to transform a vector in the space of the independent variables defining the DNA curve ("control" points) to a vector in the space of the actual curve (DNA) points. Because the millisecond simulations are computationally intensive, a 12-processor Power Challenge computer and efficient parallel strategies will be employed. To measure characteristic times related to slithering, the PI's will use three-dimensional graphics tools to analyze interparticle distance and curvature time-evolution, and thus determine the scaling of site juxtaposition times with DNA size. The computational modeling of this project will complement experiments and provide insight into the vital role of supercoiled DNA in replication, recombination, and transcription. The algorithms developed here are general and can be applied to a wide range of other important biomolecular problems. |
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1998 — 2001 | Schlick, Tamar | R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Dna Supercoiling--Macroscopic Modeling @ New York University The three objectives of this theoretical study of DNA supercoiling are: (1) Developing a general dynamic scheme capable of millisecond simulations for a macroscopic polymer subject to hydrodynamics modeled by curve-fitting techniques. (2) Developing an extension of the homogeneous, elastic rod energy model for dynamic simulations of DNA to incorporate sequence and protein-binding effects. (3) Studying systematically the global structural and dynamic features of DNA associated with site juxtaposition, the rate at which two sites along the DNA come into close spatial proximity as a result of supercoiling; this general problem has many applications to genetic processes where juxtaposition is a prerequisite for the reaction and where DNA supercoiling plays mechanistic roles, such as transcription regulation, recombination, and topoisomerase activity. Unfortunately, it is very difficult to study these fast processes by instrumentation. Our juxtaposition simulations will be performed for average-sequence DNA, plasmids of specific composition, and DNA bound to proteins, with a major focus on site-synapsis kinetics in the recombination of resolvase. The studies will help clarify the role of supercoiling in processes involving supercoiled DNA and DNA/protein interactions: How does supercoiling enhance juxtaposition with respect to linear DNA, and how do juxtaposition times depend on the site separation, DNA length, salt concentration, DNA sequence, and bound proteins? Simulations will also address specific biological hypotheses of supercoiled-directed mechanisms concerning the experimentally-measured dependence of synapsis on the superhelical density, the failure of synapsis for nicked circular DNA, the indispensability of supercoiling in site-specific recombinations where three sites synapse but not two, the orientation selectivity in recombination reactions that depend on supercoiling, the fast and topologically-specific juxtaposition in resolvase, and the kinetics of site synapsis in resolvase. New modeling and simulation protocols for studying biologically interesting processes of supercoiled DNA in solution that are large-scale and long-time will also result. The global characteristics of the double helix explored here - interactions among distant DNA sites, supercoiling dynamics and energetics - play important roles in the action of the metabolically essential enzymes that interact with DNA. Further progress in our understanding of superhelicity has many practical benefits: Understanding the dependence of juxtaposition rates on external and internal factors might also ultimately help design conditions to enhance recognition among sites within long DNA and hence also between DNA and proteins. The fundamental importance of DNA topoisomerases associated with supercoiling and knotting has led to much research on topoisomerase inhibitors that act as anticancer or antibacterial drugs. Thus, any new structural and dynamic information on supercoiling and DNA-protein interactions may ultimately contribute to these pharmaceutical applications. |
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2000 — 2001 | Schlick, Tamar | N/AActivity Code Description: No activity code was retrieved: click on the grant title for more information |
International Workshop: Methods For Macromolecular Modeling @ New York University Schlick |
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2000 — 2004 | Schlick, Tamar | R13Activity Code Description: To support recipient sponsored and directed international, national or regional meetings, conferences and workshops. |
Workshop On Methods For Macromolecular Modeling @ New York University DESCRIPTION (Adapted from the applicant's abstract): Computational methods are increasingly being recognized as valuable tools for the study of biomolecular structure and function. Advances in simulation techniques, most notably in the areas of conformational sampling, fast electrostatics, molecular dynamics integration, and quantum-mechanical calculations are having significant impact on structural biology. New algorithmic approaches, hierarchical spatial representations and improved computing platforms will continue to enhance the reliability of macromolecular simulations and increase their applicability and relevance to biomedical research. The purpose of the multidisciplinary Workshop on Methods for Macromolecular Modeling M3 - the third in a series of Workshops (1994: Lawrence, Kansas; 1997: Berlin, Germany) - is to bring together both developers of computational tools for biomolecular simulations and those biological and chemical scientists who utilize (or are interested in applying) computer modeling to macromolecular problems. The Workshop will be held at the Courant Institute of Mathematical Sciences of NYU on October 12-14 and co-sponsored by the Society for Industrial and Applied Mathematics (SIAM) as part of SIAM's new Activity Group in the Life Sciences. The topics to be highlighted in M3 2000 are: (1) new methods for long-term molecular dynamics simulations; (2) conformational sampling - equilibrium and nonequilibrium processes; (3) multiscale modeling; (4) quantum/classical mechanics; (5) fast electrostatics; and (6) applications to enzyme catalysis, DNA modeling, and DNA/protein systems. The program will provide a timely and unique opportunity for close interaction and scientific exchange among biomolecular researchers, computer scientists, and applied mathematicians. In the era of structural and functional genomics, and much more integrative science on the horizon (e.g., proteomics, cellomics), such synergy will kindle new ideas and help educate young scientists for cross-disciplinary research at the interface of computational science and biology. The program will emphasize the application of computational methods to problems of medical relevance, such as the consequences of protein folding advances to disease mechanisms and to drug design. The assessment of current progress and the identification of future directions will be accomplished through a "Perspectives" session at the end of the Workshop, a report of which will be prepared. Articles by invited speakers will be collected in Springer Verlag's Lecture Notes series in Computational Science & Engineering (LNCSE), edited by selected members of the organizing committees. These tangible records, in addition to a carefully designed program, are expected to serve the community and the funding agencies by educating junior scientists at disciplinary interfaces, stimulating new ideas in computational techniques for biomedical modeling, and identifying key areas for future research. |
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2002 — 2009 | Schlick, Tamar | N/AActivity Code Description: No activity code was retrieved: click on the grant title for more information |
Toward Rna Genomics: a Pilot Study in the Analysis, Design, and Prediction of Rna Structures @ New York University We propose a pilot study to analyze, design, and predict RNA structures using a combination of graph theory and computational methods. The design and prediction work aims to expand the set of RNA sequences and structures available, and hence our knowledge of RNA functions. By representing RNA secondary structures as tree or pseudoknot graphs, we exploit the mathematical results in graph theory for graph comparison, enumeration, and construction. This approach allows us to enumerate all possible RNA graphs which may represent both natural and hypothetical RNA topologies. Our proposed investigations consist of three related stages: (1) survey and analyze existing RNAs; (2) design RNA sequences for novel RNA tree topologies; and (3) predict the three-dimensional structures of designed RNA sequences. In survey and analysis (goal 1), we will systematically search for the occurrence of RNAs within a larger RNA system, especially for ribosome structures; use RNA topological characteristics to survey and classify functional RNA families; and develop graph theory algorithms to estimate the probable size and diversity of various functional RNA groups within genomes. Our RNA search tools, survey results, and classification methods will be made available to the public through the Nucleic Acid Database. To generate novel RNA topologies for three-dimensional structure prediction (goal 2), we will apply two strategies: sequence mutation of known RNAs and de novo sequence design. Finally, our goal of predicting the three-dimensional structures of designed sequences (goal 3) will be accomplished through the development of empirical force fields and folding algorithms for reduced RNA models. For this challenging goal, we will consider several computational approaches, including the use of elastic energy models with Brownian dynamics as employed for long DNAs. |
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2003 — 2010 | Schlick, Tamar | R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Dna Supercoiling: Local and Global Aspects @ New York University DESCRIPTION (provided by applicant): Understanding chromosome organization and its control of gene expression represents one of the most fundamental open biological challenges. Genomic organization and expression are intimately related because the complex structure and dynamics of DNA and protein-bound DNA at a large range of spatial and temporal scales regulate basic processes of life, such as the movement of mobile genetic elements ("mobile DNA") like plasmids or transposons, and transcription initiation. Mobile DNAs are transferred among bacterial pathogens and can propagate bacterial pathogenicity (through virulence genes), as well as drug resistance. While the acquisition of mobile DNAs is only the first of many stages in the evolution of specialized pathogens such as plague, E. coli, cholera, and anthrax, it has been hypothesized that common mechanisms are responsible for regulating intercellular gene transfer in many pathogens. In eukaryotic transcription, the first step in protein synthesis, RNA synthesis can only proceed when the DNA is accessible: through a complex network of nucleosome modifications, variant histones, and remodeling, it is hypothesized that eukaryotic genomes alter states of folding and compaction of the chromatin fiber to control DNA access and, as such, orchestrate (recruit or repress) transcription as needed. Many details of mobile DNA transfer and chromatin organization are unknown. The goal of the proposed work is to elucidate structural/dynamical mechanisms associated with such regulatory control in the transfer of mobile DNAs within genomes and in chromatin organization following histone modifications. Our long-term goals are to integrate structural and dynamics aspects of chromatin organization and regulation with transcription initiation to delineate thermodynamic mechanisms involved. Both processes combine regulatory local protein/DNA interactions with global responses in large systems of protein-bound supercoiled DNA. Based on models and applications completed under prior support, we will integrate protein/DNA conformations at atomic resolution on the nanosecond scale with global aspects of site juxtaposition in supercoiled DNA on the millisecond scale through mesoscale models (which incorporate local details where needed and macroscopic features where possible). Our aims are to: 1) test/delineate the local conformational changes hypothesized to repress transposition in specific transposase monomer, dimer, and inhibitor complexes; 2) determine effects of plasmid superhelicity, DNA interwound conformations, and mobile DNA size on site synapsis times and juxtaposition mechanisms in very long DNA, and thereby estimate the probability of DNA transfer to complement traditional biochemical and genetic approaches to propagation of microbial virulence; and 3) delineate hypothesized crucial electrostatic effects of two sequence variants of histone H2 and modified tails of histones H3 and H4 on chrornatin organization. Resulting insights can ultimately be exploited to design conditions that might limit mobile DNA propagation and hence microbial pathogen spread, or affect transcription initiation, such as enzymes that regulate DNA super coiling and nucleosome composition and pharmaceutical compounds that interfere with synaptic complexes and chromatin folding/unfolding rearrangements. |
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2003 — 2012 | Mishra, Bhubaneswar (co-PI) [⬀] Shapley, Robert (co-PI) [⬀] Osman, Roman Shelley, Michael [⬀] Greengard, Leslie (co-PI) [⬀] Schlick, Tamar |
N/AActivity Code Description: No activity code was retrieved: click on the grant title for more information |
Igert: Program in Computational Biology (Cob) @ New York University Many achievements in the biological and biomedical sciences are fueled by advances in technology and computational science. To address the complex challenges in the biological sciences in the 21st century, there is a growing need for professionals who can translate scientific problems in biology into mathematics and computations; for such productive work, familiarity with modern scientific computing approaches as well as key biological challenges is essential. |
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2003 — 2013 | Schlick, Tamar | N/AActivity Code Description: No activity code was retrieved: click on the grant title for more information |
@ New York University Studying large-scale, long-time biological processes such as enzyme catalysis, protein folding, and macromolecular assembly is a challenging task in computational biophysics. Since these processes occur over microseconds to seconds, much beyond the scope of traditional dynamics simulations, new techniques are needed to provide insights into detailed, local motions to supplement experiments. In this project, funded jointly by the Molecular Biophysics Program in the Division of Molecular and Cellular Biosciences and the Computational Math Program in the Division of Mathematical Sciences, the PI will develop, compare, and apply two rigorous and complementary path-generation methods, Elber's stochastic path approach (SPA) and Chandler's transition path sampling (TPS), to study the conformational transitions between closed and open states for human DNA polymerase beta (pol beta) complexed with DNA template/primer. This millisecond process is thought to be key in maintaining DNA synthesis fidelity. With these new tools, the PI will pursue several fundamental biological questions related to DNA synthesis fidelity, including the identification of slow conformational steps that steer the enzyme toward the chemistry-competent state and determination of rate-limiting steps in the enzyme's pathway. Atomic-level mechanistic insights, as well as associated free-energy barriers, will be delineated and related to enzyme function. The methodology developed is widely applicable to many other fundamental processes in molecular biophysics, and the biological findings will provide atomic-level interpretations to puzzling experimental variations in catalytic rates and error frequencies. Thus, the biological findings will help interpret fundamental fidelity mechanisms employed by DNA polymerases to replicate and repair DNA faithfully from one generation to the next. |
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2004 — 2007 | Zhang, Yingkai (co-PI) [⬀] Zhang, John Bacic, Zlatko (co-PI) [⬀] Tuckerman, Mark [⬀] Schlick, Tamar |
N/AActivity Code Description: No activity code was retrieved: click on the grant title for more information |
Acquisition of Large-Scale Parallel Computational Resources For Biological and Materials Modeling @ New York University With support from the Major Research Instrumentation (MRI) Program, the Department of Chemistry at New York University will acquire large-scale parallel computational resources for biological and materials modeling. This equipment will enhance research in a number of areas including a) the application of novel conformational sampling tools to protein structure prediction; b) modeling of DNA polymerase mechanisms; c) studies of metalloenzyme mechanisms; d) analysis of protein-ligand binding; e) accurate treatment of hydrogen-bond dynamics in supramolecular complexes; f) materials design for proton-exchange membranes; g) computationally aided design of novel RNAs; and h) development of linear scaling electronic structure algorithms. |
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2005 — 2007 | Schlick, Tamar | R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
@ New York University DESCRIPTION (provided by applicant): DNA polymerases are essential for maintaining genomic order during DNA replication and repair and thus for the long-term survival of a species. When DNA damage arising from a variety of exogenous and endogenous sources (e.g. environmental chemicals and radiation, smoking, thermal aberrations) is not accurately repaired, it can lead to human diseases like colon, lung, or skin cancer and premature aging. Thus, understanding polymerase fidelity mechanisms in DNA synthesis represents a fundamental biological and biomedical challenge. The fidelity of DNA polymerases broadly refers to their ability to incorporate correct rather than incorrect nucleotides complementary to the template DNA; such fidelities span a wide range, from 1 to nearly 10(E6) errors per one million nucleotides incorporated. Based on extensive structural and kinetic data as well as theoretical studies for several DNA polymerases, we hypothesize that high fidelity enzymes tightly orchestrate the assembly of the active site prior to nucleotide incorporation, while lower fidelity polymerases have a more flexible active site and thus a distinct assembly process; characteristic differences in the electrostatic environment and plasticity of the binding pocket likely result. Since static crystallographic structures and kinetic experimental studies of DNA polymerases cannot describe complete dynamic and energetic effects of the active site, dynamics simulations are well poised, and critically needed, to complement polymerase experimental results. In our collaborative project between an experimental and theoretical team, we will investigate systematically at atomic resolution how the conformational changes and nucleotide incorporation (chemical) pathways for higher-fidelity (pol beta) and low-fidelity (Dpo4) polymerases dictate different steering mechanisms, and how the template base, incoming nucleotide, key protein residues, and lesion-modified DNA affect the binding pocket electrostatic environment/plasticity and thus fidelity. These aims will be achieved by a combination of long-time molecular dynamics simulations and novel methodologies (transition path sampling, stochastic path approach, principal component analysis, and mixed quantum-classical mechanics methods) and an iterative design between theory and experimentation for testing, validating, and expanding these hypotheses. In particular, by delineating complete reaction profiles (conformational change and chemistry) for correct and incorrect basepairs in pol beta and relating them to experimentally-determined catalytic efficiencies and fidelity values, we will propose the rate-limiting step, orchestration of the active site assembly, and fidelity mechanisms involved and subsequently test them by experiments on mutant systems. Moreover, we will test our hypothesis that subtle conformational changes in Dpo4's thumb and little finger domains are closely associated with Dpo4's low-fidelity and lesion bypassing mechanisms, which are likely distinct than pol beta's. Our long term goals are to bridge macroscopic polymerase structures and kinetic measurements regarding catalytic efficiency, fidelity, and nucleotide binding affinity to better understand fidelity mechanisms of DNA polymerases, including response to oxidative damage and other lesions. Such studies have immediate applications to the diagnostics, and eventually treatment via polymerase inhibitors, of human diseases caused by defective repair of DNA, like various cancers and premature aging. |
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2006 | Schlick, Tamar | R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
@ New York University DESCRIPTION (provided by applicant): DNA polymerases are essential for maintaining genomic order during DNA replication and repair and thus for the long-term survival of a species. When DNA damage arising from a variety of exogenous and endogenous sources (e.g. environmental chemicals and radiation, smoking, thermal aberrations) is not accurately repaired, it can lead to human diseases like colon, lung, or skin cancer and premature aging. Thus, understanding polymerase fidelity mechanisms in DNA synthesis represents a fundamental biological and biomedical challenge. The fidelity of DNA polymerases broadly refers to their ability to incorporate correct rather than incorrect nucleotides complementary to the template DNA; such fidelities span a wide range, from 1 to nearly 10(E6) errors per one million nucleotides incorporated. Based on extensive structural and kinetic data as well as theoretical studies for several DNA polymerases, we hypothesize that high fidelity enzymes tightly orchestrate the assembly of the active site prior to nucleotide incorporation, while lower fidelity polymerases have a more flexible active site and thus a distinct assembly process; characteristic differences in the electrostatic environment and plasticity of the binding pocket likely result. Since static crystallographic structures and kinetic experimental studies of DNA polymerases cannot describe complete dynamic and energetic effects of the active site, dynamics simulations are well poised, and critically needed, to complement polymerase experimental results. In our collaborative project between an experimental and theoretical team, we will investigate systematically at atomic resolution how the conformational changes and nucleotide incorporation (chemical) pathways for higher-fidelity (pol beta) and low-fidelity (Dpo4) polymerases dictate different steering mechanisms, and how the template base, incoming nucleotide, key protein residues, and lesion-modified DNA affect the binding pocket electrostatic environment/plasticity and thus fidelity. These aims will be achieved by a combination of long-time molecular dynamics simulations and novel methodologies (transition path sampling, stochastic path approach, principal component analysis, and mixed quantum-classical mechanics methods) and an iterative design between theory and experimentation for testing, validating, and expanding these hypotheses. In particular, by delineating complete reaction profiles (conformational change and chemistry) for correct and incorrect basepairs in pol beta and relating them to experimentally-determined catalytic efficiencies and fidelity values, we will propose the rate-limiting step, orchestration of the active site assembly, and fidelity mechanisms involved and subsequently test them by experiments on mutant systems. Moreover, we will test our hypothesis that subtle conformational changes in Dpo4's thumb and little finger domains are closely associated with Dpo4's low-fidelity and lesion bypassing mechanisms, which are likely distinct than pol beta's. Our long term goals are to bridge macroscopic polymerase structures and kinetic measurements regarding catalytic efficiency, fidelity, and nucleotide binding affinity to better understand fidelity mechanisms of DNA polymerases, including response to oxidative damage and other lesions. Such studies have immediate applications to the diagnostics, and eventually treatment via polymerase inhibitors, of human diseases caused by defective repair of DNA, like various cancers and premature aging. |
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2007 — 2013 | Gan, Hin Hark Schlick, Tamar |
N/AActivity Code Description: No activity code was retrieved: click on the grant title for more information |
Computational Methods For Tertiary Rna Folding and Novel Rna Design @ New York University Project Abstract (NSF 0727001) |
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2009 — 2011 | Schlick, Tamar | N/AActivity Code Description: No activity code was retrieved: click on the grant title for more information |
Workshop Proposal: Imag Futures Meeting @ New York University It is now an opportune time to assess the current state of modeling in biomedical, biological and behavioral research. In 2003, a small trans-agency working group resulted in the formation of the Inter-agency Modeling and Analysis Group (IMAG) and the first inter-agency solicitation for |
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2009 — 2012 | Schlick, Tamar | R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Computational Studies of in Vitro Selection of Rnas @ New York University DESCRIPTION (provided by applicant): Project Summary/Abstract. Synthetic RNAs discovered via in vitro selection experiments have wide-ranging applications in biomedical sciences and biotechnology, including therapeutic aptamers that inhibit protein function and ribozymes that control gene expression. The RNA in vitro selection process, however, lacks systematic computational analysis to potentially increase the probability of discovering complex synthetic RNAs. To fill this significant gap, we have developed computational approaches for designing structured RNA pools and optimizing RNA functions to improve the productivity of in vitro selection and directed evolution experiments. In vitro selection experiments and our computational analysis suggest that designed RNA pools possessing diverse structural motifs can enhance discovery of complex RNA motifs which are rarely found in random pools. This is the main hypothesis we aim to demonstrate and apply in this proposal. To address current limitations and develop computational in vitro selection, we aim to develop: (Aim A) computational approaches to structured RNA pool design; (B) methods for screening and testing designed RNA pools; and (Aim C) a computational approach for simulating directed evolution for optimizing RNA functions. In Aim A, we will develop structured pool design approaches that allow generation of user-defined target structures with constant binding or catalytic motifs using a Monte Carlo simulation method. In Aim B, we will computationally test the performance of designed pools using motif scanning and screening (e.g., PI's SVD/TNPACK software tools) methods. In addition, we will experimentally verify that designed pools are superior to random pools via a collaboration with Luc Jaeger, an expert on RNA in vitro selection and nanotechnology. In Aim C, we will develop a computational approach to in vitro evolution by combining the motif scanning/screening methods, the nucleotide transition (mixing) matrix approach, and the partial least squares method for accumulating beneficial mutations to model RNA motif selection and mutagenic PCR procedures; optimized RNA candidates from our computational in vitro evolution scheme will be experimentally tested by Jaeger's lab. With these algorithmic developments and experimental collaboration, we expect that our computational approaches to pool design and analysis and directed evolution will provide a comprehensive resource to assist experimentalists in designing better in vitro selection experiments and optimizing RNA functions for demanding biomedical applications such as discovering high-binding affinity aptamers targeting proteins in cancer and other diseases. Our project also provides continued excellent interdisciplinary training of students in computational biology, chemistry mathematics, and biomedicine. PUBLIC HEALTH RELEVANCE: Project Narrative Synthetic RNAs discovered via in vitro selection and directed evolution experiments have wide-ranging biological and biomedical applications, including therapeutic RNAs that modulate disease-related proteins. Our work is based on the hypothesis that designed structured RNA libraries are better than random pools for discovering complex RNAs. Our project will develop and test computational approaches for designing structured RNA pools and enhancing directed evolution to assist experimentalists in discovering complex RNAs. We will interact with experimental biomedical researchers to exploit and extend our methods' capabilities for advancing the development of molecular tools for biomedical applications. |
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2011 — 2014 | Schlick, Tamar | R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Modeling Rna Tertiary Structure Folding by a Hierarchical Framework @ New York University DESCRIPTION (provided by applicant): RNA molecules are important cellular components involved in many fundamental biological roles. Because the structural features of RNA are intimately connected to their biological function, there is great interest in predicting RNA structure from sequence. The proposed research addresses both RNA structure prediction - development of a hierarchical modeling approach using graph theory and statistical tools, and RNA design - engineering fluorescent riboswitches that can sense transcription termination, offering researches visualization of the process in vivo. The proposed approach requires development of new mathematical and statistical/computer science tools for sampling RNA graph objects efficiently in 3D - to provide an initial, coarse level of sampling - and for developing systematically structure-based statistical approaches to score RNA conformations using data-mining tools. Extensive analysis of RNA junction motifs based on known structures will be used to develop separate local and global statistical potentials to predict both local geometric orientations, as well as global long-range interactions. These RNA models and associated potentials will be combined and carefully tested in three inter-related stages of folding in the following hierarchical design: (1) Explore RNA's structural conformation space coarsely using MC sampling on tree graphs that represent RNA 2D structures embedded in 3D lattices with statistical potentials that select RNA-like conformations; (2) Improve prediction accuracy using a coarse-grained three-bead-per-nucleotide model with a higher-level statistical potential to guide 3D assembly; and (3) Refine the best candidates using dynamics simulations on full atomistic models with force-field potentials. After careful analysis followed by development and testing of the new mathematical tools, each stage of the plan will be refined to finally integrate the components. New design applications for fluorescent riboswitches will be pursued, by marrying known elements of fluorescent aptamers with ligand-based configurational rearrangements of riboswitches that control gene expression. |
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2011 — 2015 | Schlick, Tamar | R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Modeling Chromatin Organization and Function @ New York University DESCRIPTION (provided by applicant): Understanding chromosome organization and its control of gene expression represents one of the most fundamental and significant open biological challenges. Modeling the folding states of chromatin on various spatial and temporal scales is key for unraveling the most basic cellular functions, including transcription activation, gene silencing, and epigenetic control. In this proposal, we continue our innovative modeling project on chromatin modeling started in 2000 that has provided novel and high-impact publications concerning chromatin organization and dynamics to incorporate new factors that expand the model scope and impact significant biological problems. We also add an experimental collaborator, Dr. Sergei Grigoryev, with whom we have already worked successfully, [and a team at Stanford's Simbios National Center for Biomedical Computation, to help disseminate our software tools and enhance our project's impact.] Our long term goal is to integrate structural and dynamical aspects of chromatin organization to delineate the thermodynamic mechanisms of transcriptional regulation mediated through protein factors, epigenetic marks, and environmental conditions. To advance in this goal, we will study: (Aim 1) chromatin structure and folding with multivalent ions and dynamic ionic distribution; (Aim 2) chromatin secondary structure folding under different internal and external factors; (Aim 3) tertiary chromatin organization with divalent ions, chromatin fiber concentration, and architectural proteins. In Aim 1, we will develop a rigorous model of chromatin folding with multivalent ions by using a combination of Poisson-Boltzmann theory, an improved representation of screening potential functions, and a method for computing screening potentials as the chromatin conformation changes. In Aim 2, we will explore the effects in the structure of the 30-nm chromatin fiber of DNA linker length variability, histone variants, epigenetic modifications and external forces [using an innovative combination of mesoscale, multiresolution and all-atom models.] In Aim 3, we will model tertiary chromatin structures induced by multivalent ions, concentrated fiber environments, and bound proteins to unravel the structural mechanisms for fiber-fiber interactions and fiber-loop formation and advance our understanding of transcriptional control via large-scale alterations of chromatin folds. These challenging studies in delineating chromatin organization, energetic, and dynamics examined with innovative modeling and experimental techniques, will help elucidate key structure/function connections that fundamentally regulate genomic organization and expression. The experimental collaboration with Dr. Grigoryev will help integrate experiment and theory; [the collaboration with Dr. R. Altman at Stanford's Simbios will help disseminate our developed tools and enhance project impact.] The developed models and methods are applicable to other complex macromolecules systems. Ultimately, this work's results have practical applications by impacting design of agents that control nucleosome composition and chromatin folds. |
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2014 — 2016 | Pyle, Anna Marie (co-PI) [⬀] Schlick, Tamar |
R13Activity Code Description: To support recipient sponsored and directed international, national or regional meetings, conferences and workshops. |
Telluride Workshop On Challenges in Rna Structural Modeling and Design @ New York University DESCRIPTION (provided by applicant): The heightened appreciation for the central role of RNA molecules in all cellular processes - from catalysis to control of gene expression to cellular differentiation - combined with the practical applications of synthetic RNAs in biomedicine and biomolecular engineering have raised new challenges regarding RNA structure analysis, prediction, and design to both experimental and theoretical scientists. These challenges have produced many innovative approaches, including interdisciplinary efforts, to analyze, predict, simulate, and design RNA molecules. While many successes have been reported, progress in the field has been hampered by limited experimental resolution and an incomplete understanding of RNA tertiary structure, especially for large RNAs. Though RNA structure is believed to be hierarchical, the difficult problem of understanding and predicting its tertiary structure from its primary as well as secondary structure remains unsolved in general. In addition, some database issues and limited coordination of RNA archives have emerged. To advance this important scientific frontier, we will hold TSRC meetings in Summers 2014 and 2016 to bring leading experimentalists and modelers to discuss and advance the field. We aim to create a core working group to bring together scientists working on both the genomic and molecular levels of RNA using novel experimental, mathematical, statistical, and computational methods. By familiarizing scientists from disparate disciplines with the challenges, and presenting current efforts, advances, and ideas, we hope to catalyze new approaches and collaborations in this important field, identify gaps in knowledge and areas for progress, and address these gaps after the first meeting via focused problems by the second meeting in 2016. Support by the NIH will help not only improve the workshop, but also provide NIH direct feedback on the participants' dialog and outcomes via resulting meeting reports and direct communications. |
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2017 — 2021 | Schlick, Tamar | R35Activity Code Description: To provide long term support to an experienced investigator with an outstanding record of research productivity. This support is intended to encourage investigators to embark on long-term projects of unusual potential. |
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2020 — 2021 | Schlick, Tamar | N/AActivity Code Description: No activity code was retrieved: click on the grant title for more information |
Rapid: Exploring Covid-19 Rna Viral Targets by Graph-Theory-Based Modeling @ New York University The urgently needed treatments and vaccines for COVID-19 rely on a fundamental understanding of the complex viral apparatus. This project will determine the structural properties and drug-binding potential of two regions of the viral RNA essential for invasion and propagation of the COVID-19 genome in host cells: genes responsible for making spike and fusion proteins. Specifically, the project will develop new and efficient graph-theory based computational algorithms for identifying subregions in the COVID-19 viral genome that alter the RNA substructure when they are mutated. Identification of these subregions will aid in the discovery of anti-viral inhibitor compounds. Graph theory tools already developed in the PI?s lab offer coarse-grained approaches for RNA structural analysis and design. The PI will combine these tools with biomolecular modeling to examine the therapeutic potential of anti-viral inhibitors known from SARS, MERS, and other viruses. This project will produce structural insights into the RNA viral regions and identify critical nucleotides and candidate inhibitors that will help make progress against COVID-19. The research has profound impact to COVID-19 as well as other coronaviruses that could emerge in the future. The project offers unique interdisciplinary training in mathematics, biology, chemistry, and scientific computing for young scientists, including women and minorities. The research results will be shared rapidly with the COVID-19 research community at large. |
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