# Modeling the influence of translation-elongation kinetics on protein structure and function

> **NIH NIH R35** · PENNSYLVANIA STATE UNIVERSITY, THE · 2021 · $374,424

## Abstract

Project Summary
An emerging paradigm in molecular biology is that translation kinetics can influence nascent protein behavior.
Introducing synonymous codon mutations into an mRNA molecule, which changes the rate at which codon
positions are translated by the ribosome but not the amino acids they encode, has been shown to influence
whether a nascent protein will fold and function, misfold and malfunction, aggregate, or efficiently translocate
to a different cellular compartment. The genomes of different species use synonymous codons with different
frequencies, suggesting that mRNA molecules may encode an additional layer of information to guide the
variation in translation speed across a coding sequence and thereby influence the fate of a protein. Indeed,
synonymous mutations that can change translation rates have now been linked to a variety of diseases,
including subtypes of hemophilia and cancer. These findings are a shift away from the prevailing view that a
protein's amino acid sequence alone encodes its structure and function to one in which the kinetics of protein
synthesis are relevant to in vivo protein behavior. As the coupling been translation kinetics and nascent protein
behavior has been relatively understudied, many fundamental biological questions about this phenomenon
remain unanswered. These questions include: what are the molecular origins of codon translation rates? How
can we model the influence of translation elongation kinetics on protein structure and function? How do
changes in translation speed lead to the experimentally observed changes in the folding and function of the
Cystic Fibrosis Transmembrane Conductance Regulator protein and the clock protein KaiB? In this research
program, a range of computational tools will be developed and applied to address these questions. These tools
include coarse-grained molecular dynamics simulations, chemical kinetic modeling, and bioinformatics
techniques. Such computational tools are well-suited to address these questions as they provide a means to
simulate protein synthesis at the molecular level, explore the impact of changing codon translation rates on
nascent protein folding and function, and extract molecular information relevant to translation kinetics from
Next-Generation Sequencing data sets. Additionally, a number of anticipated findings from this research will
be tested by our experimental collaborator. This proposal will advance the nascent proteome field by
examining details of these biomolecular systems that are difficult to measure experimentally, by providing
molecular explanations for experimental observations, and by challenging the field's current paradigms to
motivate entirely new research directions.

## Key facts

- **NIH application ID:** 10237895
- **Project number:** 5R35GM124818-05
- **Recipient organization:** PENNSYLVANIA STATE UNIVERSITY, THE
- **Principal Investigator:** Edward Patrick O'Brien
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $374,424
- **Award type:** 5
- **Project period:** 2017-08-01 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10237895

## Citation

> US National Institutes of Health, RePORTER application 10237895, Modeling the influence of translation-elongation kinetics on protein structure and function (5R35GM124818-05). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10237895. Licensed CC0.

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