Thursday, December 26, 2024
12/26/2024
Computational Enzymology to Study Diverse Catalytic Strategies of RNA PI: Darrin M. York, Rutgers University, Piscataway, NJ 08854-8087 USA. RNA enzymes (ribozymes) are fundamental in biology, and have important applications in chemistry, biotech- nology and medicine. The scientific community is still in early stages of discovery, and the full breadth of poten- tially transformative RNA and related nucleic acid based technology and therapeutics have yet to be realized. A critical barrier to progress toward this realization is the lack of a predictive understanding of ribozyme mechanisms that can be used to guide design. This proposal addresses this critical barrier by the creation of new enabling technology to study RNA enzymes (Aim 1) that will be applied to small self-cleaving (nucleolytic) ribozymes (Aim 2), and artificially engineered self-alkylating and methyltransferase ribozymes and a naturally occurring group I intron ribozyme (Aim 3). Predictive insight gained from these studies will unveil general principles crucial for our understanding of RNA catalysis and the rational design of new ribozyme-based biomedical technology. Aim 1 will create advanced tools for computational RNA enzymology, including 1) new fast/accurate quan- tum+machine learning force fields for RNA catalysis, 2) integrated software for inclusion of nuclear quantum effects, and 3) robust methods for determination of reaction paths and free energy surfaces (including corrections to expensive high-level ab initio surfaces). These methods are significant as enabling technology to study mech- anisms of RNA catalysis. The goal of this aim is develop innovative technology designed to meet the needs of the driving ribozyme applications in Aims 2 and 3, as well as many applications outside the scope of the proposal. Aim 2 will apply our computational enzymology tools to study the catalytic mechanisms of small nucleolytic ribozymes (Psr, HHr and HDVr) and a related artificially engineered DNAzyme (8-17dz). These systems are important as tools for chemical and molecular biology, and as tractable models for RNA/DNA catalysis. The goal of this aim is to apply and further develop general principles for RNA-cleaving nucleic acid enzyme design, building on our L-platform/L-scaffold framework for naturally occurring “G+A” and “G+M” ribozyme classes. Aim 3 will explore mechanisms of artificially engineered self-alkylating ribozyme (SAR) and methyl transferase ribozyme (MTR1), and the naturally occurring Tetrahymena group I intron (THr) ribozyme. These systems have far-reaching implications for biotechnology and medicine. The goal of this aim is to examine the extent to which design principles can be extended and transferred to these systems to provide deeper insight into the diverse array of catalytic strategies available to nucleic acid enzymes. Working together, these aims will accomplish the overarching goal to achieve a predictive understanding of ribozyme mechanisms that can be used to guide the design of new technology and therapeutics.
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