# Sequence and Environmental Determinants of the Protein Energy Landscape

> **NIH NIH R35** · UNIVERSITY OF CALIFORNIA BERKELEY · 2024 · $446,560

## Abstract

All proteins sample a diverse array of conformations (folded, unfolded, and excited states) with differing
free energies and dynamics depending on the environmental conditions. We can now predict a structural model
for the folded state given the amino acid sequence. The sequence of a protein, however, encodes much more
than just this native structure – it encodes the entire energy landscape – an ensemble of conformations whose
populations (energetics) and dynamics are finely tuned and critical for proper function and cellular health. A
major hurdle in going from sequence to function is our lack of understanding of the non-native regions of the
landscape. These high-energy conformations are important for directing the stability, dynamics and folding of a
protein, and modulations of this ensemble play a role in misfolding, protein signaling, catalytic activity, and
allostery. A compromised landscape, due to either changes in the cellular milieu, intrinsic genetic defects, or the
cumulative effects of cellular stresses, has been linked to disruption of proteostasis, resulting in varying
misfolding diseases and pathologies.
 Rare and transient conformations are, by their very nature, difficult to study. For decades, biophysical
chemists (including the PI) have been probing these fluctuations with high-level technologies using purified
proteins in a test tube. The test tube, however, is very different from the cell. In vivo, proteins live in a crowded
cellular environment, subject to quality control machinery, cellular modifications and subject to non-equilibrium
effects such as protein synthesis and degradation. In order to take full advantage of the wealth of detailed,
quantitative biophysical data available from in vitro studies, we need to understand how cellular factors and the
cellular environment modulate the energetics and dynamics. Such complex settings, however, are inaccessible
to the standard toolbox used for quantitative biophysical studies.
 The PI is an expert in the area of protein folding and dynamics, having devoted most of her career to
developing and utilizing sophisticated technologies to probe rare and transient conformations, both at the single
molecule and ensemble level. This current proposal focuses on: 1) understanding how these states are
modulated by features in the cell, such as co-translational folding, post-translational modifications, and 2)
understanding how the dynamics of conformational changes are controlled at the sequence level. The long-
term goal is a is a molecular, quantitative, and predictive understanding of the relationship between sequence
and the energy landscape, together with a predictive understanding of how the environment modulates this
landscape.

## Key facts

- **NIH application ID:** 10848313
- **Project number:** 5R35GM149319-02
- **Recipient organization:** UNIVERSITY OF CALIFORNIA BERKELEY
- **Principal Investigator:** SUSAN MARQUSEE
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $446,560
- **Award type:** 5
- **Project period:** 2023-06-01 → 2028-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10848313

## Citation

> US National Institutes of Health, RePORTER application 10848313, Sequence and Environmental Determinants of the Protein Energy Landscape (5R35GM149319-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10848313. Licensed CC0.

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