# Macromolecular dynamics and conformational changes in biological function

> **NIH NIH R35** · COLUMBIA UNIVERSITY HEALTH SCIENCES · 2022 · $559,114

## Abstract

Conformational changes of proteins are required for nearly all biological functions and inappropriate
conformational transitions are associated with numerous pathologies. Comprehensive experimental
information on the essential contributions of intramolecular dynamics and intermolecular kinetics to biological
functions of proteins is critical for biophysical theories of equilibrium properties, such as heat capacity and
thermal stability; for mechanistic interpretations of kinetic processes, such as enzyme catalysis and ligand
recognition; for understanding “action at a distance” in allostery or regulation; and for design of novel proteins
and protein ligands, including pharmaceutical agents. Conformational changes in proteins, including local
librations, loop 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. Mutations that perturb dynamical processes and conformational equilibria are associated
with significant pathology, including loss or gain of function and misfolding. 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
between theory and experiment in interpreting results, formulating hypotheses for on-going investigation, and
improving both experimental and theoretical techniques. The present proposal will use these approaches to
explicate the functional roles of conformational transistions in enzymes, including ribonuclease HI (and other
members of the nucleotidyl-transferase superfamily), the DNA-repair protein AlkB, and the RNA exosome;
Hox transcription factors and other nucleic acid binding proteins; and protein-protein interactions, including
strand-swapping and dimerization by cadherin cell-adhesion proteins. These objectives are supported by
development of improved approaches for characterizing protein dynamics by NMR spectroscopy and MD
simulation. This research program will explicate at a level of unprecedented detail molecular features and
principles underlying conformational changes, dynamics, and kinetics that are critical for understanding
normal and abnormal biological functions of proteins and other macromolecules. Completion of these goals
will enable ...

## Key facts

- **NIH application ID:** 10318591
- **Project number:** 5R35GM130398-04
- **Recipient organization:** COLUMBIA UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** ARTHUR G PALMER
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $559,114
- **Award type:** 5
- **Project period:** 2019-01-01 → 2023-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10318591

## Citation

> US National Institutes of Health, RePORTER application 10318591, Macromolecular dynamics and conformational changes in biological function (5R35GM130398-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10318591. Licensed CC0.

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