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Related Concept Videos

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Cooperative allosteric transitions can occur in multimeric proteins, where each subunit of the protein has its own ligand-binding site. When a ligand binds to any of these subunits, it triggers a conformational change that affects the binding sites in the other subunits; this can change the affinity of the other sites for their respective ligands. The ability of the protein to change the shape of its binding site is attributed to the presence of a mix of flexible and stable segments in the...
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Proteins are dynamic macromolecules that carry out a wide variety of essential processes; however, the activities of most proteins depend on their interactions with other molecules or ions, known as ligands.
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Allosteric proteins have more than one ligand binding site; the binding of a ligand to any of these sites influences the binding of ligands to the other sites. When a protein is allosteric, its binding sites are called coupled or linked.  In the case of enzymes, the site that binds to the substrate is known as the active site and the other site is known as the regulatory site. When a ligand binds to the regulatory site, this leads to conformational changes in the protein that can influence...
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Updated: Jun 11, 2025

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Expanding Automated Multiconformer Ligand Modeling to Macrocycles and Fragments.

Jessica Flowers1, Nathaniel Echols1, Galen Correy1

  • 1Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, CA.

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Summary
This summary is machine-generated.

Ligands can exist in multiple shapes (conformations) even after binding to proteins. Improved software, qFit-ligand, now better models these diverse ligand shapes using enhanced sampling, aiding drug design.

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Area of Science:

  • Structural biology
  • Computational chemistry
  • Drug discovery

Background:

  • Small molecule ligands display conformational flexibility in solution and can retain some flexibility upon protein binding.
  • Current structural models often represent only a single ligand conformation, potentially overlooking important conformational heterogeneity.
  • Previous computational methods for modeling ligand conformations had limitations, including non-physical results and inability to handle complex molecules like macrocycles.

Purpose of the Study:

  • To introduce an improved version of qFit-ligand with enhanced conformational sampling capabilities.
  • To extend qFit-ligand for analyzing alternative ligand conformations in high-throughput X-ray crystallography data.
  • To better characterize residual conformational heterogeneity in ligand-bound protein structures for improved drug design.

Main Methods:

  • Implemented stochastic conformational sampling using RDKit routines within qFit-ligand.
  • Extended qFit-ligand to process PanDDA-modified density maps from fragment screening.
  • Evaluated the new qFit-ligand version by comparing its fits to electron density and assessed torsional strain against existing models.

Main Results:

  • The enhanced qFit-ligand successfully samples a wider range of low-energy conformations for both small molecules and macrocycles.
  • The improved software demonstrates better fitting to electron density and reduced torsional strain compared to previous versions and single-conformer models.
  • qFit-ligand can now effectively identify alternative ligand conformations in data from high-throughput fragment screening experiments.

Conclusions:

  • The improved qFit-ligand provides a more accurate representation of ligand conformational heterogeneity in structural models.
  • This enhanced ability to model diverse ligand conformations offers valuable insights for the rational design of therapeutic agents.
  • The advancements facilitate a deeper understanding of ligand-protein interactions and conformational dynamics.