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Related Concept Videos

Ligand Binding Sites02:40

Ligand Binding Sites

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.
Protein-ligand interactions are quite specific; even though numerous potential ligands surround a cellular protein at any given time, only a particular ligand can bind to that protein. Moreover, a ligand binds only to a dedicated area on the surface of the protein, known as the...
Conserved Binding Sites01:49

Conserved Binding Sites

Many proteins’ biological role depends on their interactions with their ligands, small molecules that bind to specific locations on the protein known as ligand-binding sites. Ligand-binding sites are often conserved among homologous proteins as these sites are critical for protein function.
Binding sites are often located in large pockets, and if their location on a protein’s surface is unknown, it can be predicted using various approaches. The energetic method computationally analyses the...
Ligand Binding and Linkage00:49

Ligand Binding and Linkage

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 the...
Cooperative Allosteric Transitions01:58

Cooperative Allosteric Transitions

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...
Drug-Receptor Bonds01:25

Drug-Receptor Bonds

Drug-receptor bonds are formed through various chemical forces when drugs interact with target cells. Covalent bonds, strong and irreversible, are exemplified by DNA-alkylating anticancer agents that inhibit cell division. However, such irreversible drug binding lacks selectivity and can modify the DNA of the surrounding healthy cells. Covalent binding often contributes to tissue toxicity, as seen with chloroform and paracetamol metabolites binding to the liver, causing hepatotoxicity.
In...
Noncovalent Attractions in Biomolecules02:35

Noncovalent Attractions in Biomolecules

Noncovalent attractions are associations within and between molecules that influence the shape and structural stability of complexes. These interactions differ from covalent bonding in that they do not involve sharing of electrons.
Four types of noncovalent interactions are hydrogen bonds, van der Waals forces, ionic bonds, and hydrophobic interactions.
Hydrogen bonding results from the electrostatic attraction of a hydrogen atom covalently bonded to a strong-electronegative atom like oxygen,...

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Related Experiment Video

Updated: Jul 14, 2026

Structure-Guided Design and Development of Novel Cyclophilin A Inhibitors and Ganoderiol-F Derivatives: An In-Silico Approach
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Structure-Guided Design and Development of Novel Cyclophilin A Inhibitors and Ganoderiol-F Derivatives: An In-Silico Approach

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Ligand binding and circular permutation modify residue interaction network in DHFR.

Zengjian Hu1, Donnell Bowen, William M Southerland

  • 1Department of Biochemistry and Molecular Biology, Howard University College of Medicine, Washington, District of Columbia, United States of America.

Plos Computational Biology
|June 19, 2007
PubMed
Summary

Investigating dihydrofolate reductase (DHFR) variants reveals that disrupting folding elements impacts network communication crucial for catalysis. Ligand binding modifies these networks, enhancing communication through the cofactor.

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Structure-Guided Design and Development of Novel Cyclophilin A Inhibitors and Ganoderiol-F Derivatives: An In-Silico Approach
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Optimization of Synthetic Proteins: Identification of Interpositional Dependencies Indicating Structurally and/or Functionally Linked Residues
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Optimization of Synthetic Proteins: Identification of Interpositional Dependencies Indicating Structurally and/or Functionally Linked Residues

Published on: July 14, 2015

Area of Science:

  • Biochemistry
  • Structural Biology
  • Computational Biology

Background:

  • Enzyme catalysis, specifically in dihydrofolate reductase (DHFR), relies on intricate residue interaction networks and dynamic loop motions.
  • Understanding how protein structure and ligand interactions modulate these networks is key to enzyme function.

Purpose of the Study:

  • To investigate the impact of ligand binding and altered chain connectivity on network communication within DHFR.
  • To analyze the effects of breaking chain connections in both folding and non-folding regions on DHFR's network properties.

Main Methods:

  • Systematic network analysis of DHFR's residue interaction network.
  • Molecular dynamics simulations of native DHFR and 19 circularly permuted variants.
  • Analysis of network properties, including shortest paths and centrality measures.

Main Results:

  • Chain cleavage in folding element regions significantly perturbs network properties near the active site, potentially deactivating DHFR.
  • The protein active site is strategically located near residues central to the shortest paths in the interaction network.
  • Ligand binding induces 'network-bridging effects,' altering network pathways to predominantly pass through the cofactor and shortening average shortest paths.

Conclusions:

  • Disrupting structural elements in DHFR can impair its catalytic function by altering essential network communication.
  • Ligand binding plays a critical role in modulating DHFR's internal network dynamics, optimizing communication pathways for catalysis.