# Translation Kinetics and their Effects on Protein Structure and Function, mRNA half-lives, and Cellular Phenotype

> **NIH NIH R35** · PENNSYLVANIA STATE UNIVERSITY, THE · 2024 · $423,419

## Abstract

Project Summary
Translation kinetics critically influences protein structure and function, the rate of mRNA degradation, and
cellular phenotype. When synonymous codon mutations are incorporated into an mRNA molecule (which
changes the rate at which codon positions are translated by the ribosome but not the amino acids they encode)
the specific activity of enzymes changes for long time periods, mRNA degradation rates are altered when these
mutations lead to ribosome traffic jams, and the ability of cells to migrate and maintain a circadian rhythm can
be affected. These effects occur across species, from bacteria to fruit flies, from fungi to humans. What is
missing in this field is a comprehensive, molecular understanding of how translation kinetics influences these
processes. Utilizing both computational (theory, simulation, and big data) and experimental (Mass Spec, Cryo-
EM, and NMR) methods, this proposal focuses on four fundamental questions: (i) Can the existence of a novel
form of protein misfolding, which is suggested to link synonymous mutations and altered protein function, be
experimentally demonstrated? (ii) Can gene expression be altered when such protein misfolding occurs in
transcription factors? (iii) Is it possible to understand and predict how elongation kinetics give rise to different
patterns of ribosome traffic, and how these patterns influence translation-dependent mRNA degradation? (iv)
What molecular mechanisms connect synonymous mutations in humans to changes in growth phenotype?
 Preliminary data suggest clear hypotheses to these questions. For questions (i) and (ii), synonymous
mutations are hypothesized to alter the kinetic partitioning of nascent protein molecules into subpopulations of
misfolded, soluble, self-entangled states that have reduced functionality, which can affect catalysis in the case
of enzymes or DNA promotor binding in the case of transcription factors. For question (iii), application of
interpretable machine learning has suggested molecular factors that can alter both ribosome traffic and mRNA
degradation – which will form the basis for follow up in silico and in vivo testing. And for question (iv),
rigorous statistical methods the PI has used have identified synonymous cancer drivers which provide a unique
opportunity to understand and connect synonymous mutations to cellular phenotype. These hypotheses will be
tested using computational tools including multi-scale simulation techniques, bioinformatics, and machine
learning. And experimentally tested using mass spectrometry, Cryo-EM, NMR, and enzymatic chemotaxis.
 This research will establish a unifying mechanism by which synonymous mutations can alter soluble
protein structure and function over long time periods. It will provide a novel molecular basis by which
synonymous mutations can affect gene expression at the transcriptional level. It will result in a predictive
model connecting non-linear effects between translation kinetics, ribosome traffi...

## Key facts

- **NIH application ID:** 10932839
- **Project number:** 5R35GM124818-07
- **Recipient organization:** PENNSYLVANIA STATE UNIVERSITY, THE
- **Principal Investigator:** Edward Patrick O'Brien
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $423,419
- **Award type:** 5
- **Project period:** 2017-08-01 → 2028-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10932839

## Citation

> US National Institutes of Health, RePORTER application 10932839, Translation Kinetics and their Effects on Protein Structure and Function, mRNA half-lives, and Cellular Phenotype (5R35GM124818-07). Retrieved via AI Analytics 2026-08-11 from https://api.ai-analytics.org/grant/nih/10932839. Licensed CC0.

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