# Biophysical and structural studies of protein and enzyme mechanism, evolution, and engineering

> **NIH NIH R35** · FRED HUTCHINSON CANCER CENTER · 2024 · $616,000

## Abstract

Project Summary/Abstract
Among the several ongoing revolutions in biological research, two (the ability to visualize increasingly complex
biomolecular machines and assemblages and the ability to create novel protein structures and corresponding
functions) represent the foundation of our laboratory's research program. For many years, we have divided its
activities between (i) determining the structures, mechanisms and biological roles of gene targeting proteins
and base modifying enzymes, and (ii) employing protein engineering to create new protein folds, assemblages,
and functions, and to test our understanding of protein form and function. We now plan to renew and expand
upon our research mission by address several questions and problems in the fields of nucleic acid
enzymology, molecular recognition, and protein engineering.
The first two projects will build upon our experience studying and engineering homing endonucleases (also
called `meganucleases'). In doing so, we will answer questions surrounding the evolution, recognition
mechanisms and engineerability of (i) sequence-specific microbial RNA endonucleases and (ii) eukaryotic
retrotransposons. We plan to leverage our basic studies of these systems to create new tools for
transcriptomic analyses and genome engineering, respectively. The third project addresses a current
challenge in protein engineering: the accurate design of biomolecular interfaces that rely heavily on
stereospecific hydrogen-bond networks to facilitate the balance of affinity, specificity and reversibility that is a
hallmark of biomolecular interactions and regulation. To do so, we will create and then couple together protein-
protein and protein-small molecule binding functions through the creation of novel synthetic ligand-induced
protein multimerization systems. The project will contribute to the field of molecular design and engineering by
optimizing strategies for the accurate design of stereospecific hydrogen bond networks for that facilitate
protein-protein and protein-ligand recognition and binding.

## Key facts

- **NIH application ID:** 10851691
- **Project number:** 5R35GM148166-02
- **Recipient organization:** FRED HUTCHINSON CANCER CENTER
- **Principal Investigator:** BARRY L. STODDARD
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $616,000
- **Award type:** 5
- **Project period:** 2023-06-01 → 2028-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10851691

## Citation

> US National Institutes of Health, RePORTER application 10851691, Biophysical and structural studies of protein and enzyme mechanism, evolution, and engineering (5R35GM148166-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10851691. Licensed CC0.

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