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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...
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...
The Equilibrium Binding Constant and Binding Strength02:18

The Equilibrium Binding Constant and Binding Strength

The equilibrium binding constant (Kb) quantifies the strength of a protein-ligand interaction. Kb can be calculated as follows when the reaction is at equilibrium:
Protein-protein Interfaces02:04

Protein-protein Interfaces

Many proteins form complexes to carry out their functions, making protein-protein interactions (PPIs) essential for an organism's survival. Most PPIs are stabilized by numerous weak noncovalent chemical forces. The physical shape of the interfaces determines the way two proteins interact. Many globular proteins have closely-matching shapes on their surfaces, which form a large number of weak bonds. Additionally, many PPIs occur between two helices or between a surface cleft and a polypeptide...
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...

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Modeling Ligands into Maps Derived from Electron Cryomicroscopy
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Modeling Protein-Ligand Binding by Mining Minima.

Wei Chen1, Michael K Gilson, Simon P Webb

  • 1VeraChem LLC, Germantown, MD.

Journal of Chemical Theory and Computation
|May 29, 2012
PubMed
Summary
This summary is machine-generated.

The mining minima algorithm accurately predicts protein-small molecule binding free energies for HIV-1 protease and PDE10A inhibitors, with Poisson-Boltzmann correction being key. This computational method shows promise for drug discovery.

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Area of Science:

  • Computational chemistry
  • Molecular modeling
  • Drug discovery

Background:

  • Protein-small molecule interactions are crucial for drug development.
  • Accurate prediction of binding free energies remains a challenge.
  • Existing methods often simplify protein or solvent flexibility.

Purpose of the Study:

  • To apply the mining minima algorithm for the first time to protein-small molecule binding.
  • To evaluate the accuracy of this end-point approach using empirical force fields and implicit solvent models.
  • To identify critical components of the model for improving prediction accuracy.

Main Methods:

  • Utilized the mining minima algorithm with an empirical force field and implicit solvent.
  • Treated protein binding sites as fully flexible.
  • Estimated free energies by summing over local energy wells.
  • Validated against experimental data for HIV-1 protease and phosphodiesterase 10a inhibitors.

Main Results:

  • Achieved encouraging agreement with experimental binding free energy data.
  • Identified the Poisson-Boltzmann correction as the most critical factor for accuracy.
  • Observed computed configurational entropy changes consistent with previous host-guest system studies.
  • Analyzed the strengths and weaknesses of the computational approach.

Conclusions:

  • The mining minima algorithm is a promising tool for predicting protein-small molecule binding free energies.
  • Further enhancements in accuracy and speed are feasible.
  • The method provides insights into binding thermodynamics, including entropy-energy correlations.