# Molecular Mimics of Protein Tertiary Folding from Primary Sequence Information

> **NIH NIH R01** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2020 · $303,971

## Abstract

PROJECT SUMMARY
 Proteins are the central functional instruments that enable life, and the development of strategies for
protein mimicry is a grand challenge for chemists. Artificial backbones with defined folding propensities,
termed “foldamers”, can offer biostable analogues of natural entities; however, challenges related to design
create barriers to mimicking complex tertiary folds. Overcoming this barrier promises to open a new frontier
and advance foldamers toward the functional versatility of proteins.
 With support from the initial award, a general method for creating foldamer tertiary structure was
developed based on the systematic alteration of backbone covalent structure in natural sequences. An
important gap remains in establishing the ability of these mimetics to reproduce and modulate functional
properties of prototype proteins on which they are based. A long-term goal of the PI’s research program is
to develop principles for the design of artificial backbones capable of reproducing the full panoply of protein
folds and functions in nature and to apply these principles to control properties such as folded structure,
folded stability, physiological stability, and dynamics. The overall objective of this renewal application is to
demonstrate the scope of functions possible in heterogeneous-backbone foldamer tertiary structure
mimetics. The central hypothesis guiding this work is that design principles developed in the initial award
period can be applied to produce functional analogues of diverse prototype proteins and also used to tune
functional characteristics of the native backbone. The rationale for pursuing the proposed research is that
pushing beyond structural mimicry to functional mimicry in protein-inspired artificial scaffolds will hone
design principles, create valuable bioactive agents, and shed new light on natural systems.
 In order to test the above central hypothesis, two specific aims will be pursued: (1) develop mimics of
zinc finger proteins with native-like molecular recognition characteristics; (2) create mimics of disulfide-rich
domains from insect and reptile venoms.
 In terms of expected outcomes, the proposed work will (1) expand the scope of foldamer tertiary
structure mimicry (complex chain topologies, large multidomain proteins); (2) broaden the functional
repertoire of these scaffolds (selective recognition of DNA, proteins, and biological membranes); (3) yield
new insights into the dynamics of sequence-specific DNA binding by zinc finger proteins; and (4) provide a
starting point toward bioactive agents with potential applications in the management of chronic pain and
treatment of microbial infections. Collectively, realization of the goals of the project will lead to a vertical
advance in the size, structural complexity, and functional diversity possible in synthetic protein mimetics.

## Key facts

- **NIH application ID:** 9861247
- **Project number:** 5R01GM107161-07
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** WILLIAM SETH HORNE
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $303,971
- **Award type:** 5
- **Project period:** 2013-07-01 → 2023-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9861247

## Citation

> US National Institutes of Health, RePORTER application 9861247, Molecular Mimics of Protein Tertiary Folding from Primary Sequence Information (5R01GM107161-07). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9861247. Licensed CC0.

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