# Macromolecular dynamics and conformational changes in biological function

> **NIH NIH R35** · COLUMBIA UNIVERSITY HEALTH SCIENCES · 2024 · $628,140

## Abstract

PROJECT SUMMARY
Conformational changes of proteins are required for nearly all biological functions and inappropriate
conformational transitions are associated with numerous pathologies, including gain or loss of function
mutations, misfolding diseases, and pathogen drug resistance mutations. Comprehensive experimental
information on intramolecular dynamics and intermolecular kinetics is critical for biophysical understanding of
structure/function relationships; for mechanistic interpretations of kinetic processes, such as enzyme catalysis
and ligand recognition; for understanding “action at a distance” in allostery or regulation of activity; and for
design of novel proteins and protein ligands, including pharmaceutical agents. Conformational changes in
proteins, including local librations, loop and hinge motions, relative motions between domains, collective
“breathing” of protein cores, ligand-binding or oligomerization reactions, and overall folding-unfolding events,
may be closely coupled, and in some instances rate-limiting, to biological functions such as molecular
recognition, transitions along the catalytic cycle of enzymes, and inhibition or activation of proteins through
intra- or inter-molecular protein-protein interactions. Recent developments, including those from the PI
laboratory, have opened new opportunities for investigation of conformational dynamic processes using NMR
spin relaxation measurements (and other NMR observables) at equilibrium in solution and with atomic site
resolution, without potential complications introduced by non-native modifications necessary for other solution-
state spectroscopic techniques. In addition, close coupling between experimental measurements and
molecular dynamics (MD) simulations or other theoretical approaches allow feedback with experiment in
interpreting results, formulating hypotheses for on-going investigation, and improving both experimental and
theoretical techniques. The present proposal will use NMR spectroscopic and computational approaches to
explicate the functional roles of conformational transitions in enzyme catalysis, including ribonuclease HI (and
other members of the nucleotidyl-transferase superfamily) and the DNA-repair protein AlkB; in DNA recognition
by transcription factors, including Hox and bZip proteins; and in protein-protein molecular recognition
interactions, including strand-swapping and dimerization by cadherin cell-adhesion proteins. The biological
goals are based on recent advances in the PI laboratory (i) establishing a quantitative relationship between
active-site loop dynamics and enzyme activity for ribonuclease HI homologs, (ii) describing a multi-state
coupled folding and binding mechanism for dimerization of cadherin proteins, and (iii) identifying both pre-
formed and induced conformations of transcription factors and target DNA in tuning selectivity and affinity.
Completion of these goals will provide exquisite insight into strucuture/dynamics/functiona...

## Key facts

- **NIH application ID:** 10765404
- **Project number:** 2R35GM130398-06
- **Recipient organization:** COLUMBIA UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** ARTHUR G PALMER
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $628,140
- **Award type:** 2
- **Project period:** 2019-01-01 → 2029-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10765404

## Citation

> US National Institutes of Health, RePORTER application 10765404, Macromolecular dynamics and conformational changes in biological function (2R35GM130398-06). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10765404. Licensed CC0.

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