Related Experiment Video
Updated: Jun 9, 2025
10:58
Protein WISDOM: A Workbench for In silico De novo Design of BioMolecules
Published on: July 25, 2013
17.0K
Accurate protein-ligand binding free energy estimation using QM/MM on multi-conformers predicted from classical
Farzad Molani1, Art E Cho2,3
1Department of Bioinformatics, Korea University, Sejong, Korea.
Communications Chemistry
|October 29, 2024
Summary
We developed new computational protocols combining QM/MM and M2 methods for accurate prediction of binding free energy. This approach offers a cost-effective and generalizable alternative to existing methods for drug design.
Area of Science:
- Computational Chemistry
- Structural Biology
- Drug Discovery
Background:
- Accurate prediction of binding free energy is essential for rational drug design.
- Understanding protein-ligand interactions is key to developing effective therapeutics.
Purpose of the Study:
- To develop and validate novel computational protocols for predicting binding free energies.
- To assess the performance of these protocols across diverse protein-ligand targets.
Main Methods:
- Developed four protocols combining Quantum Mechanics/Molecular Mechanics (QM/MM) calculations with the Mining Minima (M2) method.
- Applied protocols to 9 targets and 203 ligands, including conformational search and QM/MM-derived charge parameterization.
- Utilized a differential evolution algorithm with a universal scaling factor for free energy calculations.
Main Results:
- Achieved a high Pearson's correlation coefficient (0.81) between predicted and experimental binding free energies.
- Demonstrated generalizability across diverse targets.
- Obtained a low mean absolute error of 0.60 kcal/mol, surpassing many existing methods.
Conclusions:
- The developed QM/MM-M2 protocols provide accurate and cost-effective binding free energy predictions.
- This method is a promising tool for accelerating drug discovery and understanding molecular interactions.
- The approach offers performance comparable to advanced techniques at a reduced computational expense.
Related Concept Videos
02:18The Equilibrium Binding Constant and Binding Strength
12.8K
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:
12.8K
01:49Conserved Binding Sites
4.2K
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...
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...
4.2K
02:40Ligand Binding Sites
12.7K
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...
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...
12.7K
00:49Ligand Binding and Linkage
4.8K
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...
4.8K
01:58Cooperative Allosteric Transitions
7.9K
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...
7.9K
02:04Protein-protein Interfaces
12.5K
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...
12.5K