Collaborative research: nucleobase-modified PNA for sequence selective triple-helical recognition of non-coding RNA

This $360,000 Project Grant award from the National Science Foundation's (NSF) Mathematical and Physical Sciences program (CFDA 47.049) supports collaborative research by professors Eriks Rozners of SUNY at Binghamton and James A. Mackay of Elizabethtown College. The project aims to develop new peptide nucleic acid (PNA) molecules capable of selectively recognizing and binding to double-stranded non-coding RNA. This research addresses an important challenge in RNA biochemistry and could enable advancements in the fundamental understanding of non-coding RNA as well as practical applications in biotechnology and synthetic biology. The award period runs from August 2024 to July 2027. No sub-awards are planned for this grant.

Abstract

With the support of the chemistry of life processes (CLP) program in the division of chemistry, professors eriks rozners of suny at binghamton and james a. Mackay of elizabethtown college are studying new methods for molecular recognition of biologically significant non-coding RNA. With the onset of biochemical technologies such as crispr-CAS9 and the challenges associated with emerging pathogens such as the sars-COV-2 virus, RNA chemistry and biochemistry is at the forefront of research. Less than 2% of DNA encodes for functional proteins, while over 70% of DNA is transcribed into RNA. The non-coding rnas play important yet not fully understood roles in regulation of biological processes. Selective recognition, imaging, and functional regulation of such rnas will be highly useful for fundamental science and practical biotechnology applications. The project is focused on uncovering new ways for targeting double-stranded RNA (dsrna), which is a long-standing problem and practical limitation in RNA biochemistry. The impact of the project will be broadened by expanding interdisciplinary collaborative research across traditional institutional boundaries and fostering the training and development of a diverse, globally competitive stem workforce through research and mentoring activities. The collaboration continues a partnership that has established a bridge for elizabethtown college (a primarily undergraduate institution) students, including women, minorities, and first-generation college students, for transitioning from undergraduate to advanced graduate studies at a research university. Work will continue toward improving stem education of undergraduate and graduate students and offer unique training for graduate students and postdoctoral researchers interested in faculty positions at primarily undergraduate institutions. The development of sequence-selective RNA binders is important for understanding the biochemistry of non-coding rnas and may strongly impact fundamental RNA biology and practical applications in biotechnology and synthetic biology. The collaborative study will focus on development of new peptide nucleic acid (PNA) nucleobases capable of recognition of any sequence of dsrna. Objective 1 develops nucleobases that could improve PI-PI stacking of the PNA strand in PNA-dsrna triplexes. Objective 2 develops extended nucleobases that could recognize the entire hoogsteen face of watson-crick base pairs of dsrna. The properties of the new pnas will be optimized using molecular modelling and dynamics simulations and synthetic organic chemistry. If successful, the project could allow molecular recognition of any sequence of dsrna and enable a variety of applications such as imaging and functional control of regulatory RNA, designer riboswitches for synthetic biology, and inhibition of biologically important RNA for fundamental studies. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the foundation's intellectual merit and broader impacts review criteria.- subawards are not planned for this award.