# Macromolecular Conformational Heterogeneity

> **NIH NIH R35** · UNIVERSITY OF MARYLAND BALTIMORE · 2021 · $722,975

## Abstract

Project Summary
Biological macromolecules exhibit an amazing degree of conformational heterogeneity as required for their
various functions. The importance of this heterogeneity is becoming more evident as different biological
functions associated with various conformational states of individual biological molecules are identified. To
investigate the conformational properties of macromolecules and facilitate the use of the information in drug
development, our laboratory has focused on a comprehensive research program that optimizes and extends
empirical force fields for biological and drug-like molecules, develops novel conformational and solute
sampling methods and applies those tools in collaborative studies on systems of therapeutic relevance. In the
proposed studies we will further optimize and extend both the additive (fixed-charge) CHARMM and
polarizable classical Drude oscillator force fields. Work on the Drude force field will involve extensions to
cover the full range of biological macromolecules and organic, drug-like molecules, continue to improve the
overall accuracy of the model, extend the model to more accurately treat ligated metals via the inclusion of local
charge transfer effects and implement improved methods for the treatment of van der Waals interactions.
Sampling methods development will extend the Hamiltonian Replica Exchange approach to enhance sampling
in oligonucleotides and polysaccharides including improved sampling of specific degrees of freedom associated
with high-energy barriers using biasing potentials. The solute sampling method developed in our laboratory
based on the oscillating μex Grand-Canonical Monte Carlo/Molecular Dynamics method will be extended to
more accurately sample the distribution of osmolytes and ions, including Mg+2, around macromolecules and
allow the approach to be used with the polarizable Drude force field. In combination, the conformational and
solute sampling approaches represent powerful methods that will allow for theoretical investigations of the
interplay between environment and macromolecular conformational heterogeneity. The developed tools will be
applied in studies on nucleic acids investigating the ionic atmosphere of DNA, exploiting solvachromatic shifts
determined using QM/MM methods, the impact of Mg+2 on the conformational heterogeneity of RNA,
including on riboswtiches and small regulatory RNAs in bacterial pathogens, and the catalytic and base
specificity mechanisms of DNA glycosylases important for base excision repair. In the area of polysaccharides,
the conformational heterogeneity of glycans acting as antigens for vaccines targeting antibiotic resistant
bacteria and for use in cancer immunotherapy will be investigated. Specific disease states to be targeted include
antibiotic resistant infections associated with Klebsiella Pneumonia and Pseudomonas Aeruginsa and cancers
accessible to immunotherapy treatment. In addition, these collaborative efforts will further validate...

## Key facts

- **NIH application ID:** 10147104
- **Project number:** 5R35GM131710-03
- **Recipient organization:** UNIVERSITY OF MARYLAND BALTIMORE
- **Principal Investigator:** ALEXANDER D MACKERELL
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $722,975
- **Award type:** 5
- **Project period:** 2019-05-01 → 2024-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10147104

## Citation

> US National Institutes of Health, RePORTER application 10147104, Macromolecular Conformational Heterogeneity (5R35GM131710-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10147104. Licensed CC0.

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