# Capturing Transient Protein and Nucleic Acid Structures During Their Functions on Multiple Spatial and Temporal Scales

> **NIH NIH R01** · NORTHWESTERN UNIVERSITY · 2020 · $347,557

## Abstract

Summary/Abstract
The long term objective of the proposed research is to develop an integrated instrumentation capable of
studying protein/nucleic acid structural dynamics that are relevant to their functions on the time scales
from femtosecond to millisecond in order to gain new insight into correlations of active site structures and
global conformations of these molecules. Snapshots of solution phase molecular structures over different
spatial scales, from sub-Ångström for active sites to several nanometers for overall conformation, will be
captured using time-resolved X-ray spectroscopy and scattering. These structural studies will be combined
with advanced molecular dynamics simulations that will generate detailed atomistic dynamics consistent
with measured scattering profiles over a wide-range of temporal scales from femtosecond to millisecond.
The proposed research is complementary to single crystal X-ray diffraction, and intends to map reaction
trajectories through three-dimensional structures as a function time in media that mimic biological
environments. In order to detect structural changes in an ensemble, reaction triggers must be designed to
create sudden environmental changes that synchronize actions of the molecules with much higher time
resolution than traditional mixing. The program has three main innovations from previous studies: 1) to
develop triggering sources beyond direct light excitation used in the past to initiate reactions to overcome
the limitation that very few biological systems related to human health are light activated for their function;
2) to develop novel sample delivery system that reduces the sample consumption by a factor of 100 and
enables many precious laboratory samples to be studied using the time-resolved X-ray methods; and 3) to
develop a combined approach in data analyses using advanced molecular dynamics simulation coupled to
time-dependent X-ray scattering data to extract structures with improved structural accuracy especially
for those coexisting species. The above innovation in methodology will allow us to investigate a number of
systems that are biologically significant for enzymatic reactions, signal sensing, protein/nucleic acid
folding/unfolding as well as lipids phase transitions. Several systems are chosen for the proposed studies
to capture transient structures of, a) local metal center and global protein conformations of cytochrome c
oxidase model proteins triggered by photodissociation of inhibitors; b) protein folding induced by calcium
ion a concentration jump; c) temperature-induced RNA conformational changes sensing signal for
translation; d) pH-dependent DNA structures for human oncogene regulation and e) pH-responsive lipid
nanocarrier assembly for anticancer drug delivery. These structural results combined with those of reaction
kinetics from optical transient spectroscopy will provide guidance for modulating protein and nucleic acid
functions via structural modifications, which will...

## Key facts

- **NIH application ID:** 10052597
- **Project number:** 2R01GM115761-06
- **Recipient organization:** NORTHWESTERN UNIVERSITY
- **Principal Investigator:** Lin X Chen
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $347,557
- **Award type:** 2
- **Project period:** 2015-07-01 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10052597

## Citation

> US National Institutes of Health, RePORTER application 10052597, Capturing Transient Protein and Nucleic Acid Structures During Their Functions on Multiple Spatial and Temporal Scales (2R01GM115761-06). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10052597. Licensed CC0.

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