# Macromolecular Conformational Heterogeneity

> **NIH NIH R35** · UNIVERSITY OF MARYLAND BALTIMORE · 2024 · $746,909

## Abstract

Project Summary
Biological macromolecules exhibit an amazing degree of conformational heterogeneity as required for their
various functions. This heterogeneity is inherent in almost all biological macromolecules and is influenced by
interactions with ions, solutes, and other macromolecules. An understanding of the conformational properties
of macromolecules and their structure-function relationships is essential to facilitate drug discovery. To this
end, our laboratory has focused on a comprehensive research program that includes optimizing and extending
empirical atomic force fields for biological and drug-like molecules, developing novel conformational and
solute sampling methods and applying those tools in collaborative studies on systems of biological and
therapeutic relevance. Biological systems to be studied include the role of Mg2+ ions in RNA folding and on
conformational ensembles of RNA, glycan conformational properties and the role of glycoproteins in immune
response involving antibodies (Ab) and Fcγ receptors such as FcγRIIIa and FcεRIγ. Interactions between Ab Fc
and FcγRIIIa and interactions between Fcγ receptors will be investigated to reveal their contribution towards
intracellular phosphorylation and downstream signaling. Methods developments will further optimize and
extend the additive (nonpolarizable) CHARMM36 and polarizable classical Drude oscillator force fields (FF).
Work on the additive FF will involve the explicit optimization of the off-diagonal Lennard-Jones (LJ) terms to
overcome limitations in the use of combining rules. Drude FF work will involve extending the coverage of
chemical space including non-standard amino acids, nucleic acids, and carbohydrates, as well as drug-like
molecules in the context of the Drude General Force Field (DGenFF). In addition, advances in the accuracy of
the Drude FF will include improved treatment of off-diagonal LJ and non-bonded Thole shielding interactions,
improved treatment of ions in biological systems, and additional optimization of the protein and nucleic acid
parameters of the FF targeting the equilibrium between folded and unfolded states of peptides and short
oligonucleotides. This optimization will use enhanced sampling to facilitate generation of conformational
ensembles required to apply parameter reweighting approaches. Improved conformational sampling of
macromolecules will be achieved using generative deep neural nets (DNN) for the identification of reaction
coordinates in conjunction with metadynamics as well as non-equilibrium simulation methods targeting
specific degrees of freedom with emphasis on oligonucleotides and polysaccharides. Our solute sampling
approach based on the oscillating chemical potential μex Grand-Canonical Monte Carlo/Molecular Dynamics
method will be extended to large systems (> 1 million atoms) through efficient use of GPUs, improved
treatment of long-range interactions, and the use of the polarizable Drude FF. These developments will be
implem...

## Key facts

- **NIH application ID:** 10841152
- **Project number:** 2R35GM131710-06
- **Recipient organization:** UNIVERSITY OF MARYLAND BALTIMORE
- **Principal Investigator:** ALEXANDER D MACKERELL
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $746,909
- **Award type:** 2
- **Project period:** 2019-05-01 → 2029-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10841152

## Citation

> US National Institutes of Health, RePORTER application 10841152, Macromolecular Conformational Heterogeneity (2R35GM131710-06). Retrieved via AI Analytics 2026-06-01 from https://api.ai-analytics.org/grant/nih/10841152. Licensed CC0.

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