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Principal Investigator: JAY PONDER
Organization: WASHINGTON UNIVERSITY
Fiscal Year: 2023
Award: $312,196
Funding agency: National Institute of General Medical Sciences
PROJECT SUMMARY/ABSTRACT
Nucleic acids (NAs) are the major information carrying molecules of life. The ability to use
computation to model the structure, dynamic and interactions of DNA and RNA is a key adjunct
to experimental study of these biomolecules. For example, pseudouridine-containing mRNA
vaccines against Covid-19 are a critical tool in battling the pandemic. DNAs, mRNAs, and
miRNAs are targets for a number of antibacterial and antiviral drugs. Design of small molecule
drugs binding to nucleic acids in the treatment of cancers and neurodegenerative diseases is
one of the hottest topics of current pharmaceutical research. Under this project, we will
investigate several key aspects of nucleic acids, and develop the polarizable multipole
AMOEBA+ model for simulation of NAs and their interactions. This new force field will be further
enhanced via coupling of a machine learning-based potential for local valence features with
classical long-range nonbonded interactions. The resulting AMOEBA+NN force field promises
chemical accuracy in the calculation of binding for NA systems. Parameters for the AMOEBA+
and AMOEBA+NN potentials will be generated using the new, automated Poltype2 package.
Implementation of the force fields into the existing GPU-capable Tinker9 molecular dynamics
software will enable state-of-the-art simulation and binding free energy estimation.
The applicability of molecular simulation to design of therapeutics is limited by efficiency and
accuracy of the calculations. The objective of this proposal is to enable routine, accurate
computation of the thermodynamics of binding of small-molecule ligands to NAs. Toward that
end, several current systems of biological relevance will be investigated, including binding of
metal ions to G-quadruplex structures, fluorogenic ligands with RNA aptamers, novel antibiotic
drugs with the FMN riboswitch, and conformational dynamics of the P5abc domain of the
Tetrahymena group I ribozyme. The structures and functions of NAs are highly dependent upon
their ionic environment. The interplay between RNA local structural dynamics and global/tertiary
folding is an intriguing question being addressed experimentally. The ability to simulate these
complex energetic effects in the design of novel small molecule drugs and synthetically modified
oligonucleotides will be an important growth area for future medical advances. Development of
the accurate and transferable next-generation AMOEBA+ and AMOEBA+NN force fields will
open new paths toward understand and prediction of the behavior of natural and designed
nucleic acid molecules.
Terms: <Acids><Address><Algorithms><Anti-Bacterial Agents><Antibacterial Agents><Antibiotic Agents><Antibiotic Drugs><Antibiotics><Antiviral Agents><Antiviral Drugs><Antivirals><Area><Binding><Biology><COVID crisis><COVID epidemic><COVID pandemic><COVID-19><COVID-19 crisis><COVID-19 epidemic><COVID-19 global health crisis><COVID-19 global pandemic><COVID-19 health crisis><COVID-19 pandemic><COVID-19 public health crisis><COVID19><COVID19 crisis><COVID19 epidemic><COVID19 global health crisis><COVID19 global pandemic><COVID19 health crisis><COVID19 pandemic><COVID19 public health crisis><CV-19><CV19><Cancer Treatment><Cancers><Carbohydrates><Cell Body><Cell Nucleus><Cells><Charge><Chemical Structure><Chemicals><Communities><Complement><Complement Proteins><Complex><Computer Models><Computer software><Computerized Models><Coupled><Coupling><D-Ribose><DNA><Data><Degenerative Neurologic Diseases><Degenerative Neurologic Disorders><Deoxyribonucleic Acid><Development><Disease><Disorder><Drug Design><Drugs><Electrostatics><Entropy><Environment><FMN><Flavin Mononucleotide><Free Energy><Future><G-Quadruplex><G-Quadruplexes DNA><G-Quartet Structures><G-Quartets><G-Tetrads><G4-DNA><Generalized Growth><Generations><Genetic Alteration><Genetic Change><Genetic defect><Genomics><Growth><Hydrogen Oxide><Hypercholesteremia><Ions><Life><Ligand Binding><Ligands><Machine Learning><Malignant Neoplasm Therapy><Malignant Neoplasm Treatment><Malignant Neoplasms><Malignant Tumor><Medical><Medication><Medicine><Messenger RNA><Metal Ion Binding><Methodology><Methods><Micro RNA><MicroRNAs><Miscellaneous Antibiotic><Modeling><Molecular><Molecular Configuration><Molecular Conformation><Molecular Dynamics Simulation><Molecular Interaction><Molecular Modeling Nucleic Acid Biochemistry><Molecular Modeling Protein/Amino Acid Biochemistry><Molecular Models><Molecular Stereochemistry><Muscular Dystrophies><Mutation><Myodystrophica><Myodystrophy><Nervous System Degenerative Diseases><Neural Degenerative Diseases><Neural degenerative Disorders><Neurodegenerative Diseases><Neurodegenerative Disorders><Neurologic Degenerative Conditions><Non-Polyadenylated RNA><Nucleic Acid Binding><Nucleic Acids><Nucleotides><Nucleus><Oligo><Oligonucleotides><Penetration><Performance><Pharmaceutic Preparations><Pharmaceutical Agent><Pharmaceutical Preparations><Pharmaceuticals><Pharmacologic Substance><Pharmacological Substance><Phosphates><Physics><Property><Proteins><Pseudouridine><Public Health><RNA><RNA Gene Products><RNA vaccine><RNA-based vaccine><Research><Riboflavin 5'-(dihydrogen phosphate)><Riboflavin 5'-Monophosphate><Riboflavin 5'-Phosphate><Riboflavin Mononucleotide><Ribonucleic Acid><Ribose><Rotation><SARS-CoV-2 epidemic><SARS-CoV-2 global health crisis><SARS-CoV-2 global pandemic><SARS-CoV-2 pandemic><SARS-CoV2 epidemic><SARS-CoV2 pandemic><SARS-coronavirus-2 epidemic><SARS-coronavirus-2 pandemic><Sampling><Severe Acute Respiratory Syndrome CoV 2 epidemic><Severe Acute Respiratory Syndrome CoV 2 pandemic><Severe acute respiratory syndrome coronavirus 2 epidemic><Severe acute respiratory syndrome coronavirus 2 pandemic><Site><Software><Specificity><Spinal Column><Spine><Structure><System><Tetrahymena><Therapeutic><Therapeutic Agents><Thermodynamic><Thermodynamics><Tissue Growth><Vertebral column><Water><Work><anti-bacterial><anti-cancer therapy><anti-viral agents><anti-viral compound><anti-viral drugs><anti-viral medication><anti-viral therapeutic><anti-virals><antibacterial><anticancer therapy><antiviral compound><antiviral medication><antiviral therapeutic><aptamer><backbone><base><bases><behavior prediction><behavioral prediction><biological systems><cancer therapy><cancer-directed therapy><combat><computational modeling><computational models><computational quantum chemistry><computational tools><computer based models><computerized modeling><computerized tools><conformation><conformational><conformational state><conformationally><conformations><corona virus disease 2019><corona virus disease 2019 epidemic><corona virus disease 2019 pandemic><coronavirus disease 2019><coronavirus disease 2019 crisis><coronavirus disease 2019 epidemic><coronavirus disease 2019 global health crisis><coronavirus disease 2019 global pandemic><coronavirus disease 2019 health crisis><coronavirus disease 2019 pandemic><coronavirus disease 2019 public health crisis><coronavirus disease crisis><coronavirus disease epidemic><coronavirus disease pandemic><coronavirus disease-19><coronavirus disease-19 global pandemic><coronavirus disease-19 pandemic><coronavirus infectious disease-19><degenerative diseases of motor and sensory neurons><degenerative neurological diseases><deploy vaccines><design><designing><developmental><distribute vaccines><drug/agent><enthalpy><experiment><experimental research><experimental study><experiments><flexibility><flexible><genome mutation><group I ribozyme><high blood cholesterol><hypercholesterolemia><improved><inorganic phosphate><insight><intermolecular interaction><mRNA><mRNA vaccine><mRNA-based vaccine><machine based learning><malignancy><miRNA><miRNAs><model-based simulation><models and simulation><molecular dynamics><molecular modeling><muscle dystrophy><neoplasm/cancer><neural network><neurodegenerative illness><new drug treatments><new drugs><new pharmacological therapeutic><new therapeutics><new therapy><next generation><next generation therapeutics><novel><novel drug treatments><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel therapeutics><novel therapy><nucleic acid structure><oligos><ontogeny><pandemic><pandemic disease><pharmaceutical><predictive tools><quantum chemistry><severe acute respiratory syndrome coronavirus 2 global health crisis><severe acute respiratory syndrome coronavirus 2 global pandemic><simulation><simulation software><small molecule><tool><vaccine deployment><vaccine distribution><vaccine roll-out><vaccine rollout>