# Solid State NMR Studies of Amyloid Proteins

> **NIH NIH R01** · MASSACHUSETTS INSTITUTE OF TECHNOLOGY · 2024 · $708,152

## Abstract

Project Summary/Abstract
The proposed research focuses on the application and development of magic angle spinning (MAS) NMR
as a tool for structural investigations of amyloid peptides and proteins. The research covers four major
topics.
A. Structure of Amyloid Peptides and Proteins
 (1) Aβ1-42 and Aβ1-40: Using 1H detected and DNP magic angle spinning (MAS) and cryoEM we plan the
 following experiments on Aβ: (a) a determination of the structure of Aβ1-40; (b) the structure of the
 pathologically important plaque seeded Aβ1-42; (c) the structure of the N-terminal tail and the binding of
 antibody Aducanumab to the tail; (d) and the structure of mutants for Aβ1-42.
 (2) Beta-2-microglobulin (β2m) and DeltaN6-β2m: We plan to determine the structure of the 93 AA β2m-DeltaN6 variant of the dialysis related amyloidosis (DRA) protein. In addition, DeltaN6 is thought to be the
 catalyst that seeds β2m plaques in-vivo. We therefore also intend to study mixtures of β2m and DeltaN6.
 (3) Amyloid polymorphism: We intend to determine the structure of the three polymorphs of the
 amyloidiogenic peptide GNNQQNY from Sup35. These are present in a consistent 1:1:1 population
 and will provide the first study of the manner in which defined structural changes alter 13C and 15N
 shifts. 1H, 13C and 17O NMR will be used to characterize the structure around the H2O molecules in
 the GNNQQNY lattice.
B. NMR methods None of the above structural studies would be possible absent NMR methods to assign
 spectra, measure distances and torsion angles, to enhance signal intensities, etc. We therefore plan
 to continue the development of the methods essential for these structural investigations. (a) We plan
 to continue these experiments by initially preparing U-17O/13C/15N GNNQQNY to further develop the
 spectroscopy and then to apply it to spectroscopy of Aβ1-42 and Aβ1-40. The experiments will employ 1H
 detection and DNP in order to optimize the sensitivity. PAR and PAIN have been essential to MAS
 NMR structure determinations but they are semiquantitative methods to measure 13C-13C and 13C-15N
 distances. Using SPINEVOLUTION software and experiments on model systems, we plan to develop
 these approaches into quantitative distance measurement techniques.

## Key facts

- **NIH application ID:** 10868697
- **Project number:** 5R01AG058504-04
- **Recipient organization:** MASSACHUSETTS INSTITUTE OF TECHNOLOGY
- **Principal Investigator:** ROBERT Guy GRIFFIN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $708,152
- **Award type:** 5
- **Project period:** 2017-08-01 → 2027-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10868697

## Citation

> US National Institutes of Health, RePORTER application 10868697, Solid State NMR Studies of Amyloid Proteins (5R01AG058504-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10868697. Licensed CC0.

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