Document text
Principal Investigator: Rhiju Das
Organization: STANFORD UNIVERSITY
Fiscal Year: 2024
Award: $250,000
Funding agency: National Institute of General Medical Sciences
PROJECT SUMMARY
The continuing discoveries of RNAs and their critical roles in cellular and viral machinery
are inspiring novel antibacterial, antitumor, antiviral, and genome-editing therapies
based on disabling, manipulating, and repurposing the RNAs involved. Unfortunately,
our poor biophysical understanding of `how RNAs work' is slowing the development of
these potentially life-saving efforts. A critical bottleneck has been the inapplicability of
crystallography, NMR, phylogenetic analysis, and biochemical methods to determine the
partly ordered conformations of non-coding RNAs in all their functional states. To resolve
this bottleneck, we are advancing experimental methods and complementary
computational approaches that give rich information sufficient to infer and engineer RNA
secondary and tertiary structures and their heterogeneous ensembles, evaluated
through community-wide blind trials, prospective compensatory mutation/rescue
experiments, and global RNA design challenges. Here, we continue research that will
rigorously address four biomedically significant problems that have so far seen limited
progress in molecular modeling efforts: the heterogeneity of RNA structures within their
native cellular and viral contexts; modeling and design of RNA's biological interactions
with proteins and other molecules, modulated by chemical modification; high-accuracy
calculation of RNA folding energetics; and the automated design of dynamic 3D RNA
structures for eventual medical applications. We will evaluate success through
continuing blind trials, independent tests by more than a dozen expert biological and
bioengineering collaborators, and through adoption of our methods and software tools by
the broader research community. In the same way that specialized structural biology
tools and computational design are establishing a firm understanding of protein behavior
and regulation, we propose that the technologies outlined here will transform our
understanding of structure in non-coding RNAs, providing a stronger basis for their
biomedical activation or disruption.
Terms: <2019 novel corona virus><2019 novel coronavirus><2019-nCoV><3-D><3-D structure><3-Dimensional><3-dimensional structure><3D><3D structure><AIDS Virus><Acquired Immune Deficiency Syndrome Virus><Acquired Immunodeficiency Syndrome Virus><Address><Adoption><Anti-Bacterial Agents><Bacteria><Behavior><Biochemical><Biological><Biomedical Engineering><Biophysics><Brain><Brain Nervous System><COVID-19 virus><COVID19 virus><Chemicals><CoV-2><CoV2><Communities><Complex><Computational toolkit><Computer Software Tools><Crystallographies><Crystallography><Development><Disabling><Disease><Disorder><Encephalon><Engineering><Functional RNA><Genetic Alteration><Genetic Change><Genetic defect><HIV><Heterogeneity><Human Immunodeficiency Viruses><LAV-HTLV-III><Life><Lymphadenopathy-Associated Virus><Medical><Methods><Modeling><Modification><Molecular Configuration><Molecular Conformation><Molecular Modeling Nucleic Acid Biochemistry><Molecular Modeling Protein/Amino Acid Biochemistry><Molecular Models><Molecular Stereochemistry><Mutation><Non-Coding><Non-Coding RNA><Non-Polyadenylated RNA><Non-translated RNA><Noncoding RNA><Nontranslated RNA><Organism><Phylogenetic Analysis><Phylogenetics><Play><Proteins><RNA><RNA Folding><RNA Gene Products><RNA Viruses><Regulation><Research><Ribonucleic Acid><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><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><Software Tools><Structure><Technology><Testing><Therapeutic Gene Editing><Time><Training><Transmission><Tumor Cell><Untranslated RNA><Vaccines><Viral><Virus-HIV><Work><Wuhan coronavirus><anti-bacterial><bio-engineered><bio-engineers><bioengineering><biologic><biological engineering><biophysical foundation><biophysical principles><biophysical sciences><blind><computational toolbox><computational tools><computational toolset><computer based prediction><computerized tools><conformation><conformational><conformational state><conformationally><conformations><coronavirus disease 2019 virus><coronavirus disease-19 virus><deep learning based neural network><deep learning neural network><deep neural net><deep neural network><design><designing><developmental><experiment><experimental research><experimental study><experiments><gene-editing therapy><genetic information><genome editing based therapy><genome editing therapy><genome editing treatment><genome editing-based therapeutics><genome mutation><hCoV19><living system><molecular modeling><nCoV2><neoplastic cell><neural network><noncoding><novel><predictive modeling><prospective><social role><software toolkit><structural biology><success><therapeutic editing><therapeutic genome editing><three dimensional><three dimensional structure><tool><transmission process><tumor>