# Understanding Evolution of Protein Function Through Design.

> **NIH NIH R35** · SYRACUSE UNIVERSITY · 2020 · $375,000

## Abstract

The work proposed in Project 1 is based on the first observation that one can design short Catalytic
AMyloid-forming Peptides (CAMPs) to catalyze chemical reactions with high efficiency in addition to their own
self-assembly. The goals of the proposed work are: 1. to understand the mechanism of peptide self-assembly
and how the resulting amyloid fibril tunes the properties of the metal ion for catalysis; 2. using 2D-IR, to
establish structural models for the CAMPs to set important structural and functional reference points for the
broad community of scientists interested in the role of amyloids in protein folding, catalysis and health. 3. to
examine the ability of CAMPs to effectively utilize different metals to catalyze redox reactions. 4. to develop
complex multidomain CAMPs with tunable structural features and degree of assembly. Development and
characterization of catalytic amyloids will advance several fields of biomedical importance. The structure-
activity relationships and structural insights generated in the proposed work will help us better understand the
mechanisms of amyloid toxicity and will improve our knowledge of the structures adopted by more complex
amyloid-forming proteins. In addition to its practical value this research program will have a profound impact on
our understanding of the fundamental aspects of catalysis.
 Project 2. The ability of pathogens to neutralize drugs via a newly developed catalytic activity is one of
the mechanisms of drug resistance. Therefore, deeper understanding of the factors that determine the ability of
proteins to catalyze new chemical transformations is of paramount importance. We aim to determine the
factors that guide evolution of protein function at a molecular level and use these principles to create catalysts
for chemical transformations not found in nature. Specifically, we will: 1. combine minimalist computational
approach with sophisticated protein engineering tools to test the limits of protein evolvability; 2. create new
protein catalysts for a number of different chemical transformations; 3. establish a new method to efficiently
guide directed evolution.
 Project 3 aims to develop a new environmentally insensitive fluorescent probe to study the mechanism
of pore formation by antimicrobial peptides and to elucidate the mechanism of proton conductance by influenza
A M2 and hepatitis C p7 ion channels. Specifically we will: 1. gain a thorough understanding of the
fluorescence characteristics of AzAla, an unnatural amino acid that contains azulene; 2. develop efficient
protocols for in vivo incorporation of AzAla into proteins; 3. use AzAla to determine the pKa values of the key
proton-conducting histidine residues in M2 and p7.

## Key facts

- **NIH application ID:** 9936378
- **Project number:** 5R35GM119634-05
- **Recipient organization:** SYRACUSE UNIVERSITY
- **Principal Investigator:** Ivan V Korendovych
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $375,000
- **Award type:** 5
- **Project period:** 2016-08-01 → 2021-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9936378

## Citation

> US National Institutes of Health, RePORTER application 9936378, Understanding Evolution of Protein Function Through Design. (5R35GM119634-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9936378. Licensed CC0.

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