# Micro Electron Diffraction of Toxic and/or Infectious Macromolecular Nanoassemblies

> **NIH NIH R35** · UNIVERSITY OF CALIFORNIA LOS ANGELES · 2024 · $409,283

## Abstract

SUMMARY
The field of structural biology is experiencing transformative change. New experimental and computational tools
are revealing a remarkable catalogue of structures with unprecedented speed. In addition to the thousands of
determined structures and the millions of new structure predictions, novel protein designs are emerging in a
flurry facilitated by a host of new machine learning approaches. In the face of all this, important gaps remain that
limit our fundamental understanding of protein structure and function, and our ability to rapidly visualize atomic
molecular structures. These gaps persist where conventional approaches have been traditionally stalled, for
example in the characterization of large, multimeric protein complexes, unknown chemical entities and dynamic
assemblies. The amyloid fold is a notable example of such a challenging area, given its long lack of atomic
resolution structures and viable therapeutics, as well as its emerging yet enigmatic role in benign physiological
processes such as phase separation by low complexity sequences. The Rodriguez lab has been at the forefront
of efforts to uncover complex amyloid structures with remarkable detail, facilitated in part by an ESI MIRA (R35
GM128867) award. That award also funded critical developments that brought to life new methods for structure
determination via MicroED. However, despite the promise of these methods, the single isolated structures they
have revealed in remarkable detail have lacked context and represent only a small part of the structural path
from single molecule to fibril. The current proposal, a renewal of R35 GM128867, builds on that successful five
year effort to characterize toxic and infectious assemblies at the atomic level and envisions three directions for
an improved structural understanding of protein assemblies: We now propose to 1. Further the development of
new tools for more accurate and rapid determination of molecular and cellular structures. 2. Advance our
fundamental understanding of highly pleiomorphic molecules, particularly those that are prone to forming large-
scale multimeric assemblies through amyloid-like interactions, in functional or pathogenic roles. 3. Chart
sequence-function relationships that allow proteins to give rise to and/or facilitate pathogenic traits through
allosteric or epistatic networks of residue level changes, particularly in acutely lethal agents. These directions
continue to elaborate rigorous approaches to molecular structure determination, while leveraging the
compendium of emerging tools for structure prediction and discovery. Hybrid approaches allow us to take on the
more ambitious challenges of charting the function of pathogenic and functional amyloids in situ, and to chart
vast functional sequence landscapes in dynamic multiprotein assemblies. Collectively, the efforts bring us closer
to the ideal of witnessing atomic structures in context and uncovering the basis for molecular processes that
underpi...

## Key facts

- **NIH application ID:** 10765275
- **Project number:** 2R35GM128867-06
- **Recipient organization:** UNIVERSITY OF CALIFORNIA LOS ANGELES
- **Principal Investigator:** Jose Alfonso Rodriguez
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $409,283
- **Award type:** 2
- **Project period:** 2018-08-01 → 2029-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10765275

## Citation

> US National Institutes of Health, RePORTER application 10765275, Micro Electron Diffraction of Toxic and/or Infectious Macromolecular Nanoassemblies (2R35GM128867-06). Retrieved via AI Analytics 2026-06-01 from https://api.ai-analytics.org/grant/nih/10765275. Licensed CC0.

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