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Principal Investigator: Tamar Schlick
Organization: NEW YORK UNIVERSITY
Fiscal Year: 2024
Award: $125,000
Funding agency: National Institute of General Medical Sciences
Bridging Disparate Structural/Functional Scales: Multiscale Modeling of Genome
Organization and of Viral RNA Frameshifting
Project Summary May 22, 2024
As advances in both experimental and computational biology lead to exciting discoveries in many fields
of biology and biomedicine today, new avenues to diagnose and treat human disease are becoming a reality.
Molecular dynamics and other simulation approaches play a key role in these connections by helping define
the underlying biophysical mechanisms, at unprecedented resolution. The PI's computational biophysics lab
focuses on solving fundamental structural and functional challenges concerning nucleic acids and their complexes
(notably chromatin and RNA), in collaboration with experimentalists, by innovative molecular models and
simulation methods using ideas from mathematics, computer science, engineering, biology, and chemistry. This
MIRA project continues to advance our fundamental understanding of genome organization and RNA motifs
using multiscale models that bridge disparate spatial and temporal scales to generate biophysical insights into
genome folding and cancer genomics, and RNA conformational landscapes/ viral mechanisms. For chromatin and
chromosomes, modeled nucleosomes and their protein complexes at atomic resolution, and chromatin fibers at the
mesoscale, will be linked to data from genome-wide and cancer epigenomics studies to determine the modulation
of chromatin higher-order structure in processes of aberrant gene expression. Specifically, we will focus on
the structural role and mechanisms of proteins (like CTCF and H1) in formation of gene loops, topologically
associated domains (TADs), and nuclear compartments in gene activation or repression in cancer cells. For RNA,
atomic-level biophysical modeling will be complemented by our topological coarse-grained graph approach for RNA
secondary structures (RAG: RNA-As-Graphs) to delineate programmed ribosomal frameshifting mechanisms in
RNA coronaviruses and other viruses, and advance the RNA motif atlas. Specifically, atomistic dynamics of
the RNA frameshifting element of SARS-CoV-2, along with evolutionary and biophysical analysis and chemical
reactivity experiments tailored to handle multiple RNA conformations will describe frameshifting transitions and
identify/test experimentally structure-altering mutations that hamper frameshifting. We will also build a virus
topology atlas and explore virus motifs from an RNA repertoire point of view, to help understand the RNA motif
universe and advance novel RNA design. The unraveled biophysical mechanisms in genome organization and RNA
frameshifting/conformational repertoire have translational ramifications for human cancers and viral infections by
coronaviruses or HIV. For cancer therapy, a targeted re-expression of silenced genes may be possible by chromatin
topological changes (e.g., loop dissolution) and RNA editing. For viral RNA infections, our structure-altering
and motion-suppressing mutants define new strategies for gene and anti-viral therapy, feasible by modern RNA
editing technologies. The resulting multidisciplinary computational paradigms are widely applicable to other
biomolecular processes and will be shared with the community at large.
Terms: <2019 novel corona virus><2019 novel coronavirus><2019-nCoV><30 nm Chromatin Fiber><30 nm Fiber><AIDS Virus><Acceleration><Acquired Immune Deficiency Syndrome Virus><Acquired Immunodeficiency Syndrome Virus><Address><Administrative Supplement><Affect><Algorithms><Anti-viral Therapy><Atlases><Award><Basic Research><Basic Science><Biological><Biology><Biophysical Process><Biophysics><Budgets><COVID-19><COVID-19 virus><COVID19 virus><CV-19><Cancer Treatment><Cancers><Chemicals><Chemistry><Chromatin><Chromatin Fiber><Chromosomes><CoV-2><CoV2><Collaborations><Communities><Complex><Computational Biology><Computer Systems><Coronaviridae><Coronaviridae Infections><Coronavirus><Coronavirus Infections><Coronavirus Infectious Disease 2019><DNA><Data><Data Storage and Retrieval><Dedications><Degenerative Disorder><Deoxyribonucleic Acid><Development><Diagnosis><Disparate><Elements><Engineering><Environment><Epigenetic><Epigenetic Change><Epigenetic Mechanism><Epigenetic Process><Equipment><Funding><Gene Activation><Gene Down-Regulation><Gene Expression><Gene Inactivation><Gene Silencing><Gene Transcription><Genes><Genetic><Genetic Alteration><Genetic Change><Genetic Materials><Genetic Transcription><Genetic defect><Genome><Grain><Graph><HIV><Higher Order Chromatin Folding><Higher Order Chromatin Structure><Higher Order Structure><Human><Human Immunodeficiency Viruses><Interruption><Investigators><Jobs><LAV-HTLV-III><Lead><Link><Lymphadenopathy-Associated Virus><Malignant Cell><Malignant Neoplasm Therapy><Malignant Neoplasm Treatment><Malignant Neoplasms><Malignant Tumor><Math><Mathematics><Medical><Medicine><Memory><Methods><Modeling><Modern Man><Modernization><Molecular><Molecular Configuration><Molecular Conformation><Molecular Dynamics Simulation><Molecular Modeling Nucleic Acid Biochemistry><Molecular Modeling Protein/Amino Acid Biochemistry><Molecular Models><Molecular Stereochemistry><Motion><Mutation><NIGMS><National Institute of General Medical Sciences><Non-Polyadenylated RNA><Nuclear><Nucleic Acids><Nucleosomes><Occupations><Pb element><Performance><Play><Process><Productivity><Professional Positions><Proteins><R-Series Research Projects><R01 Mechanism><R01 Program><RNA><RNA Conformation><RNA Editing><RNA Expression><RNA Gene Products><RNA Virus Infections><RNA viral infection><RNA, Messenger, Editing><Research Grants><Research Personnel><Research Project Grants><Research Projects><Researchers><Resolution><Ribonucleic Acid><Ribosomal Frame Shifting><Ribosomal Frameshift><Ribosomal Frameshifting><Role><SARS corona virus 2><SARS-CO-V2><SARS-COVID-2><SARS-CoV-2><SARS-CoV2><SARS-associated corona virus 2><SARS-associated coronavirus 2><SARS-coronavirus-2><SARS-related corona virus 2><SARS-related coronavirus 2><SARSCoV2><Salaries><Severe Acute Respiratory Coronavirus 2><Severe Acute Respiratory Distress Syndrome CoV 2><Severe Acute Respiratory Distress Syndrome Corona Virus 2><Severe Acute Respiratory Distress Syndrome Coronavirus 2><Severe Acute Respiratory Syndrome CoV 2><Severe Acute Respiratory Syndrome-associated coronavirus 2><Severe Acute Respiratory Syndrome-related coronavirus 2><Severe acute respiratory syndrome associated corona virus 2><Severe acute respiratory syndrome coronavirus 2><Severe acute respiratory syndrome related corona virus 2><Structure><Syndrome><System><Techniques><Technology><Testing><Transcription><Transcription Repression><Transcriptional Repression><Translational Frameshifting><Viral><Viral Diseases><Virus><Virus Diseases><Virus-HIV><Wages><Wuhan coronavirus><anti-cancer therapy><biologic><biophysical analysis><biophysical foundation><biophysical mechanism><biophysical model><biophysical principles><biophysical sciences><biophysical studies><cancer cell><cancer genomics><cancer progression><cancer therapy><cancer-directed therapy><cluster computing><computer biology><computer cluster><computer science><computing system><conformation><conformational><conformational state><conformationally><conformations><corona virus><coronavirus disease 2019><coronavirus disease 2019 virus><coronavirus disease-19><coronavirus disease-19 virus><coronavirus infectious disease-19><data grid><data retrieval><data storage><datagrid><degenerative condition><degenerative disease><design><designing><developmental><distributed computing><epigenetically><epigenomics><equipment acquirement><equipment acquisition><equipment investment><equipment procurement><equipment purchase><equipment purchasing><experience><experiment><experimental research><experimental study><experiments><gene repression><genome mutation><genome scale><genome-wide><genomewide><hCoV19><heavy metal Pb><heavy metal lead><human disease><improved><innovate><innovation><innovative><insight><instrument acquisition><instrument investment><instrument procurement><instrument purchase><instrumentation><macromolecule><malignancy><model-based simulation><models and simulation><molecular dynamics><molecular modeling><multi-scale computational modeling><multi-scale mathematical modeling><multi-scale modeling><multidisciplinary><multiscale computational modeling><multiscale mathematical modeling><multiscale modeling><mutant><nCoV2><neoplasm progression><neoplasm/cancer><neoplastic progression><novel><oncogenomics><parent grant><protein complex><resolutions><scientific computing><simulation><social role><software systems><targeted drug therapy><targeted drug treatments><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment><transcriptional silencing><tumor progression><viral RNA><viral infection><viral infectious disease treatment><virus RNA><virus infection><virus-induced disease>