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Related Concept Videos

Ligand Binding Sites02:40

Ligand Binding Sites

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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.
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...
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Ligand Binding and Linkage00:49

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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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The Equilibrium Binding Constant and Binding Strength02:18

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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:
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The hemoglobin in the blood, the chlorophyll in green plants, vitamin B-12, and the catalyst used in the manufacture of polyethylene all contain coordination compounds. Ions of the metals, especially the transition metals, are likely to form complexes.
In these complexes, transition metals form coordinate covalent bonds, a kind of Lewis acid-base interaction in which both of the electrons in the bond are contributed by a donor (Lewis base) to an electron acceptor (Lewis acid). The Lewis acid in...
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Updated: Jan 30, 2026

Protein Purification-free Method of Binding Affinity Determination by Microscale Thermophoresis
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Accurate Estimation of Ligand Binding Affinity Changes upon Protein Mutation.

Matteo Aldeghi1, Vytautas Gapsys1, Bert L de Groot1

  • 1Computational Biomolecular Dynamics Group, Max Planck Institute for Biophysical Chemistry, 37077 Göttingen, Germany.

ACS Central Science
|January 17, 2019
PubMed
Summary

Computational methods can now accurately predict how protein mutations affect ligand binding affinity, aiding in the design of new proteins for medicine and biotechnology. Combining free energy calculations and Rosetta protocols offers the best predictive accuracy.

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Area of Science:

  • Computational biology
  • Protein engineering
  • Biophysics

Background:

  • Designing proteins with specific ligand-binding functions is crucial for biomedicine and biotechnology.
  • Current protein engineering relies heavily on experimentation, limiting efficiency and understanding of molecular recognition.
  • Computational methods are needed to reduce costs and rigorously test principles of molecular recognition.

Purpose of the Study:

  • To assess computational methods for quantitatively predicting ligand binding affinity changes due to protein mutations.
  • To evaluate free energy calculations and Rosetta protocols for protein engineering optimization.
  • To investigate the impact of different force fields and computational protocols on prediction accuracy.

Main Methods:

  • Applied free energy calculations based on first-principles statistical mechanics.
  • Utilized the latest Rosetta protocols for protein mutation analysis.
  • Evaluated 134 mutations across various protein systems, considering computational efficiency and different force fields.

Main Results:

  • Both free energy calculations and Rosetta protocols quantitatively predict changes in ligand binding affinity.
  • Combining estimates from both free energy calculations and Rosetta yielded the most accurate predictions.
  • Achieved a root-mean-square error of 1.2 kcal/mol for the full benchmark set and 0.8 kcal/mol for a reproducible subset.

Conclusions:

  • Computational approaches, particularly when combined, can accurately predict the effects of protein mutations on ligand binding affinity.
  • This accuracy enables the use of computation for optimizing ligand-binding proteins and predicting drug resistance.
  • The findings pave the way for more efficient and rational design of proteins for various applications.