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Related Concept Videos

Induced-fit Model01:13

Induced-fit Model

Most chemical reactions in cells require enzymes—biological catalysts that speed up the reaction without being consumed or permanently changed. They reduce the activation energy needed to convert the reactants into products. Enzymes are proteins, that usually work by binding to a substrate—a reactant molecule that they act upon.
Enzymes exhibit substrate specificity, meaning that they can only bind to certain substrates. This is mainly determined by the shape and chemical characteristics of...
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:
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:
Crystal Field Theory - Octahedral Complexes02:58

Crystal Field Theory - Octahedral Complexes

Crystal Field Theory
To explain the observed behavior of transition metal complexes (such as colors), a model involving electrostatic interactions between the electrons from the ligands and the electrons in the unhybridized d orbitals of the central metal atom has been developed. This electrostatic model is crystal field theory (CFT). It helps to understand, interpret, and predict the colors, magnetic behavior, and some structures of coordination compounds of transition metals.
CFT focuses on...
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...

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Related Experiment Video

Updated: May 16, 2026

Development of Inhibitors of Protein-protein Interactions through REPLACE: Application to the Design and Development Non-ATP Competitive CDK Inhibitors
10:33

Development of Inhibitors of Protein-protein Interactions through REPLACE: Application to the Design and Development Non-ATP Competitive CDK Inhibitors

Published on: October 26, 2015

Charge Optimization Theory for Induced-Fit Ligands.

Yang Shen1, Michael K Gilson, Bruce Tidor

  • 1Department of Biological Engineering, Massachusetts Institute of Technology , Cambridge, Massachusetts 02139, United States ; Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology , Cambridge, Massachusetts 02139, United States.

Journal of Chemical Theory and Computation
|November 20, 2012
PubMed
Summary
This summary is machine-generated.

Charge optimization theory now accounts for induced-fit ligands, enabling more realistic design of molecules for drug discovery. This approach ensures the unbound ligand remains in its lowest energy state for accurate binding affinity predictions.

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Area of Science:

  • Computational chemistry
  • Molecular modeling
  • Drug discovery

Background:

  • Ligand design for high affinity and specificity is crucial for molecular recognition and therapeutics.
  • Charge optimization theory optimizes ligand charge for favorable binding free energy but traditionally assumes rigid ligands.
  • Rigid formulations fail for induced-fit ligands where unbound and bound conformations differ.

Purpose of the Study:

  • To extend charge optimization theory to accommodate induced-fit ligands.
  • To develop a thermodynamic framework for analyzing induced-fit binding contributions.
  • To apply the extended theory to HIV-1 protease for designing optimized ligand charge distributions.

Main Methods:

  • Developed a thermodynamic pathway analysis for induced-fit binding.
  • Introduced a constraint ensuring the unbound ligand conformation is the ground state.
  • Applied the methodology to HIV-1 protease using a validated inhibitor.

Main Results:

  • Rigid charge optimization applied to non-rigid cases yields physically unreasonable results, overstabilizing the bound conformation.
  • The extended theory with the ground state constraint produces realistic charge distributions for induced-fit ligands.
  • Electrostatic analysis indicates induced-fit binding does not inherently enhance affinity beyond optimized rigid binding.

Conclusions:

  • The extended charge optimization theory successfully models induced-fit ligands, allowing for more accurate design.
  • The methodology provides insights into the energetic impact of ligand conformational changes during binding.
  • Induced-fit binding, energetically, cannot surpass the affinity of optimized rigid binding.