I am a computational biologist working on modeling Nucleic acids and their complexes. Specifically, my group models and simulates DNA and RNA to understand structure, dynamics, and biological function. Such studies have important applications in medicine and technology.
An overview of the evolution of macroscale to mesoscale computer models for simulation of chromat... more An overview of the evolution of macroscale to mesoscale computer models for simulation of chromatin, the protein nucleic acid fiber that stores the DNA in higher organisms, is presented. Many biological questions concerning fiber structure remain a puzzle. The sheer size and range of spatial and temporal scales require tailored multiscale models. Our first-generation macroscopic models ignored histone tail flexibility but generated insights info preferred zigzag configurations and folding/unfolding dynamics. The second-generation mesoscale models incorporate histone tail flexibility, linker histones, and divalent ion effects to reveal the profound compaction induced by linker histones and the polymorphic fiber architecture at divalent salt environments, with a small fraction of the linker DNAs bent rather than straight for optimal compaction. Our chromatin model can be extended further to study many important biological questions concerning post-translational modifications, fiber di...
The structure of chromatin, affected by many factors from DNA linker lengths to posttranslational... more The structure of chromatin, affected by many factors from DNA linker lengths to posttranslational modifications, is crucial to the regulation of eukaryotic cells. Combined experimental and computational methods have led to new insights into its structural and dynamical features, from interactions due to the flexible core histone tails or linker histones to the physical mechanism driving the formation of chromosomal domains. Here we present a perspective of recent advances in chromatin modeling techniques at the atomic, mesoscopic, and chromosomal scales with a view toward developing multiscale computational strategies to integrate such findings. Innovative modeling methods that connect molecular to chromosomal scales are crucial for interpreting experiments and eventually deciphering the complex dynamic organization and function of chromatin in the cell.
The structure of chromatin, affected by many factors from DNA linker lengths to posttranslational... more The structure of chromatin, affected by many factors from DNA linker lengths to posttranslational modifications, is crucial to the regulation of eukaryotic cells. Combined experimental and computational methods have led to new insights into its structural and dynamical features, from interactions due to the flexible core histone tails or linker histones to the physical mechanism driving the formation of chromosomal domains. Here we present a perspective of recent advances in chromatin modeling techniques at the atomic, mesoscopic, and chromosomal scales with a view toward developing multiscale computational strategies to integrate such findings. Innovative modeling methods that connect molecular to chromosomal scales are crucial for interpreting experiments and eventually deciphering the complex dynamic organization and function of chromatin in the cell.
To elucidate the role of the histone tails in chromatin compaction and in higher-order folding of... more To elucidate the role of the histone tails in chromatin compaction and in higher-order folding of chromatin under physiological conditions, we extend a mesoscale model of chromatin (Arya, Zhang, and Schlick. Biophys.
An introduction into the usage of graph or network theory tools for the study of RNA molecules is... more An introduction into the usage of graph or network theory tools for the study of RNA molecules is presented. By using vertices and edges to define RNA secondary structures as tree and dual graphs, we can enumerate, predict, and design RNA topologies. Graph connectivity and associated Laplacian eigenvalues relate to biological properties of RNA and help understand RNA motifs as well as build, by computational design, various RNA target structures. Importantly, graph theoretical representations of RNAs reduce drastically the conformational space size and therefore simplify modeling and prediction tasks. Ongoing challenges remain regarding general RNA design, representation of RNA pseudoknots, and tertiary structure prediction. Thus, developments in network theory may help advance RNA biology.
IAENG international journal of computer science, 2017
Dual graphs have been applied to model RNA secondary structures with pseudoknots, or intertwined ... more Dual graphs have been applied to model RNA secondary structures with pseudoknots, or intertwined base pairs. In this paper we present a linear-time algorithm to partition dual graphs into maximal topological components called blocks and determine whether each block contains a pseudoknot or not. We show that a block contains a pseudoknot if and only if the block has a vertex of degree 3 or more; this characterization allows us to efficiently isolate smaller RNA fragments and classify them as pseudoknotted or pseudoknot-free regions, while keeping these sub-structures intact. Applications to RNA design can be envisioned since modular building blocks with intact pseudoknots can be combined to form new constructs.
The life and work of crystallography pioneer Isabella L. Karle is recounted (1921-2017), as resea... more The life and work of crystallography pioneer Isabella L. Karle is recounted (1921-2017), as researched from the literature and personal stories of colleagues and family. Her story includes her family background, education at the University of Michigan, research on the Manhattan Project, and 63 productive years at the Naval Research Laboratory. Her life-long partnership and scientific collaboration with husband Jerome Karle, 1985 Nobel Prize winner in Chemistry with Herbert Hauptman, is a big part of her story; however, Isabella has also established herself as a crystallographer extraordinaire through her Symbolic Addition Procedure to solve the phase problem, and her unique ability to solve the structures of complex biological molecules, including toxins, antibiotics, and peptides. Her rich family life with three daughters in a lake-front home, do-it-yourself attitude, and passions outside of science round up this portrait of a fascinating and brilliant woman.
At the virtual 2021 Biophysical Society (BPS) Annual meeting, we were happy to hold the first min... more At the virtual 2021 Biophysical Society (BPS) Annual meeting, we were happy to hold the first minisymposium of our newly formed subgroup, Multiscale Genome Organization (MGO). This idea for our subgroup emerged during the March/April 2019 BPS Thematic Meeting on chromatin multiscale modeling held at the picturesque Ecole des Physiques in the French Alps at Les Houches, France (Schlick 2020). Likely influenced by Mont Blanc in the background, inspiring us to be broad and ambitious, our dream — to bring together biologists, chemists, physicists, and mathematicians to discuss and launch collaborations and advance the field of chromatin structure, dynamics, function and applications through new conceptual approaches and perspectives — is now a reality. We are particularly excited about bringing together experimentalists and theoreticians/modelers and emphasizing the interplay between techniques and ideas concerning the complex multiscale features and properties of genomes, from bases to...
Histone tails and their epigenetic modifications play crucial roles in gene expression regulation... more Histone tails and their epigenetic modifications play crucial roles in gene expression regulation by altering the architecture of chromatin. However, the structural mechanisms by which histone tails influence the interconversion between active and inactive chromatin remain unknown. Given the technical challenges in obtaining detailed experimental characterizations of the structure of chromatin, multiscale computations offer a promising alternative to model the effect of histone tails on chromatin folding. Here we combine multi-microsecond atomistic molecular dynamics simulations of dinucleosomes and histone tails in explicit solvent and ions, performed with three different stateof-the-art force fields and validated by experimental NMR measurements, with coarse-grained Monte Carlo simulations of 24-nucleosome arrays to describe the conformational landscape of histone tails, their roles in chromatin compaction, and the impact of lysine acetylation, a widespread epigenetic change, on b...
The SARS-CoV-2 frameshifting RNA element (FSE) is an excellent target for therapeutic interventio... more The SARS-CoV-2 frameshifting RNA element (FSE) is an excellent target for therapeutic intervention against Covid-19. This small gene element employs a shifting mechanism to pause and backtrack the ribosome during translation between Open Reading Frames 1a and 1b, which code for viral polyproteins. Any interference with this process has profound effect on viral replication and propagation. Pinpointing the structures adapted by the FSE and associated structural transformations involved in frameshifting has been a challenge. Using our graph-theory-based modeling tools for representing RNA secondary structures, “RAG” (RNA-As-Graphs), and chemical structure probing experiments, we show that the 3-stem H-type pseudoknot (3_6 dual graph), long assumed to be the dominant structure has a viable alternative, an HL-type 3-stem pseudoknot (3_3) for longer constructs. In addition, an unknotted 3-way junction RNA (3_5) emerges as a minor conformation. These three conformations share Stems 1 and 3...
An overview of the evolution of macroscale to mesoscale computer models for simulation of chromat... more An overview of the evolution of macroscale to mesoscale computer models for simulation of chromatin, the protein nucleic acid fiber that stores the DNA in higher organisms, is presented. Many biological questions concerning fiber structure remain a puzzle. The sheer size and range of spatial and temporal scales require tailored multiscale models. Our first-generation macroscopic models ignored histone tail flexibility but generated insights info preferred zigzag configurations and folding/unfolding dynamics. The second-generation mesoscale models incorporate histone tail flexibility, linker histones, and divalent ion effects to reveal the profound compaction induced by linker histones and the polymorphic fiber architecture at divalent salt environments, with a small fraction of the linker DNAs bent rather than straight for optimal compaction. Our chromatin model can be extended further to study many important biological questions concerning post-translational modifications, fiber di...
The structure of chromatin, affected by many factors from DNA linker lengths to posttranslational... more The structure of chromatin, affected by many factors from DNA linker lengths to posttranslational modifications, is crucial to the regulation of eukaryotic cells. Combined experimental and computational methods have led to new insights into its structural and dynamical features, from interactions due to the flexible core histone tails or linker histones to the physical mechanism driving the formation of chromosomal domains. Here we present a perspective of recent advances in chromatin modeling techniques at the atomic, mesoscopic, and chromosomal scales with a view toward developing multiscale computational strategies to integrate such findings. Innovative modeling methods that connect molecular to chromosomal scales are crucial for interpreting experiments and eventually deciphering the complex dynamic organization and function of chromatin in the cell.
The structure of chromatin, affected by many factors from DNA linker lengths to posttranslational... more The structure of chromatin, affected by many factors from DNA linker lengths to posttranslational modifications, is crucial to the regulation of eukaryotic cells. Combined experimental and computational methods have led to new insights into its structural and dynamical features, from interactions due to the flexible core histone tails or linker histones to the physical mechanism driving the formation of chromosomal domains. Here we present a perspective of recent advances in chromatin modeling techniques at the atomic, mesoscopic, and chromosomal scales with a view toward developing multiscale computational strategies to integrate such findings. Innovative modeling methods that connect molecular to chromosomal scales are crucial for interpreting experiments and eventually deciphering the complex dynamic organization and function of chromatin in the cell.
To elucidate the role of the histone tails in chromatin compaction and in higher-order folding of... more To elucidate the role of the histone tails in chromatin compaction and in higher-order folding of chromatin under physiological conditions, we extend a mesoscale model of chromatin (Arya, Zhang, and Schlick. Biophys.
An introduction into the usage of graph or network theory tools for the study of RNA molecules is... more An introduction into the usage of graph or network theory tools for the study of RNA molecules is presented. By using vertices and edges to define RNA secondary structures as tree and dual graphs, we can enumerate, predict, and design RNA topologies. Graph connectivity and associated Laplacian eigenvalues relate to biological properties of RNA and help understand RNA motifs as well as build, by computational design, various RNA target structures. Importantly, graph theoretical representations of RNAs reduce drastically the conformational space size and therefore simplify modeling and prediction tasks. Ongoing challenges remain regarding general RNA design, representation of RNA pseudoknots, and tertiary structure prediction. Thus, developments in network theory may help advance RNA biology.
IAENG international journal of computer science, 2017
Dual graphs have been applied to model RNA secondary structures with pseudoknots, or intertwined ... more Dual graphs have been applied to model RNA secondary structures with pseudoknots, or intertwined base pairs. In this paper we present a linear-time algorithm to partition dual graphs into maximal topological components called blocks and determine whether each block contains a pseudoknot or not. We show that a block contains a pseudoknot if and only if the block has a vertex of degree 3 or more; this characterization allows us to efficiently isolate smaller RNA fragments and classify them as pseudoknotted or pseudoknot-free regions, while keeping these sub-structures intact. Applications to RNA design can be envisioned since modular building blocks with intact pseudoknots can be combined to form new constructs.
The life and work of crystallography pioneer Isabella L. Karle is recounted (1921-2017), as resea... more The life and work of crystallography pioneer Isabella L. Karle is recounted (1921-2017), as researched from the literature and personal stories of colleagues and family. Her story includes her family background, education at the University of Michigan, research on the Manhattan Project, and 63 productive years at the Naval Research Laboratory. Her life-long partnership and scientific collaboration with husband Jerome Karle, 1985 Nobel Prize winner in Chemistry with Herbert Hauptman, is a big part of her story; however, Isabella has also established herself as a crystallographer extraordinaire through her Symbolic Addition Procedure to solve the phase problem, and her unique ability to solve the structures of complex biological molecules, including toxins, antibiotics, and peptides. Her rich family life with three daughters in a lake-front home, do-it-yourself attitude, and passions outside of science round up this portrait of a fascinating and brilliant woman.
At the virtual 2021 Biophysical Society (BPS) Annual meeting, we were happy to hold the first min... more At the virtual 2021 Biophysical Society (BPS) Annual meeting, we were happy to hold the first minisymposium of our newly formed subgroup, Multiscale Genome Organization (MGO). This idea for our subgroup emerged during the March/April 2019 BPS Thematic Meeting on chromatin multiscale modeling held at the picturesque Ecole des Physiques in the French Alps at Les Houches, France (Schlick 2020). Likely influenced by Mont Blanc in the background, inspiring us to be broad and ambitious, our dream — to bring together biologists, chemists, physicists, and mathematicians to discuss and launch collaborations and advance the field of chromatin structure, dynamics, function and applications through new conceptual approaches and perspectives — is now a reality. We are particularly excited about bringing together experimentalists and theoreticians/modelers and emphasizing the interplay between techniques and ideas concerning the complex multiscale features and properties of genomes, from bases to...
Histone tails and their epigenetic modifications play crucial roles in gene expression regulation... more Histone tails and their epigenetic modifications play crucial roles in gene expression regulation by altering the architecture of chromatin. However, the structural mechanisms by which histone tails influence the interconversion between active and inactive chromatin remain unknown. Given the technical challenges in obtaining detailed experimental characterizations of the structure of chromatin, multiscale computations offer a promising alternative to model the effect of histone tails on chromatin folding. Here we combine multi-microsecond atomistic molecular dynamics simulations of dinucleosomes and histone tails in explicit solvent and ions, performed with three different stateof-the-art force fields and validated by experimental NMR measurements, with coarse-grained Monte Carlo simulations of 24-nucleosome arrays to describe the conformational landscape of histone tails, their roles in chromatin compaction, and the impact of lysine acetylation, a widespread epigenetic change, on b...
The SARS-CoV-2 frameshifting RNA element (FSE) is an excellent target for therapeutic interventio... more The SARS-CoV-2 frameshifting RNA element (FSE) is an excellent target for therapeutic intervention against Covid-19. This small gene element employs a shifting mechanism to pause and backtrack the ribosome during translation between Open Reading Frames 1a and 1b, which code for viral polyproteins. Any interference with this process has profound effect on viral replication and propagation. Pinpointing the structures adapted by the FSE and associated structural transformations involved in frameshifting has been a challenge. Using our graph-theory-based modeling tools for representing RNA secondary structures, “RAG” (RNA-As-Graphs), and chemical structure probing experiments, we show that the 3-stem H-type pseudoknot (3_6 dual graph), long assumed to be the dominant structure has a viable alternative, an HL-type 3-stem pseudoknot (3_3) for longer constructs. In addition, an unknotted 3-way junction RNA (3_5) emerges as a minor conformation. These three conformations share Stems 1 and 3...
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Papers by Tamar Schlick