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Conserved Binding Sites

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...

Conserved Binding Sites

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...

Protein-protein Interfaces

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...

Protein-Protein Interfaces

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...

Protein-Drug Binding: Mechanism and Kinetics

Protein-Drug Binding: Mechanism and Kinetics

Protein-drug binding refers to the interaction between drugs and proteins within the body. This binding process can occur intracellularly, involving drug interactions with enzymes or receptors within cells, or extracellularly, involving plasma proteins in the blood.
Various forces drive these interactions, including hydrogen bonds, hydrophobic interactions, ionic bonds, electrostatic interactions, and van der Waals forces. These bonds enable drugs to bind to specific sites on proteins,...

Conservation of Protein Domains Over Different Proteins

Conservation of Protein Domains Over Different Proteins

Protein domains are small structurally independent units that are part of a single amino acid chain. Although these domains are often structurally independent, they may rely on synergistic effects to perform their functions as part of a larger protein. Protein domains may be conserved within the same organism, as well as across different organisms.
A limited set of protein domains often duplicate and recombine during evolution. These domains can be organized in different combinations to form...

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Related Experiment Video

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Protein WISDOM: A Workbench for In silico De novo Design of BioMolecules

Protein WISDOM: A Workbench for In silico De novo Design of BioMolecules

Published on: July 25, 2013

A de novo protein binding pair by computational design and directed evolution.

John Karanicolas¹, Jacob E Corn, Irwin Chen

¹Department of Biochemistry, University of Washington, Seattle, WA 98195-7350, USA. johnk@ku.edu

|April 5, 2011

Summary

Researchers computationally designed novel protein-protein interfaces, achieving unprecedented binding affinity. Directed evolution further enhanced this interaction, demonstrating a powerful strategy for creating specific protein complexes.

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Computational Prediction of Amino Acid Preferences of Potentially Multispecific Peptide-Binding Domains Involved in Protein-Protein Interactions

Computational Prediction of Amino Acid Preferences of Potentially Multispecific Peptide-Binding Domains Involved in Protein-Protein Interactions

Published on: January 26, 2024

Area of Science:

Protein engineering
Computational biology
Structural biology

Background:

Designing de novo protein-protein interfaces is crucial for understanding molecular interactions.
It enables novel applications in biology and medicine.

Purpose of the Study:

To develop a computational method for designing high-affinity protein-protein complexes.
To create novel protein interfaces with native-like characteristics.

Main Methods:

A motif-based computational approach was used to design protein interfaces.
The designed proteins (Prb and Pdar) were tested for heterodimerization.
Directed evolution and X-ray crystallography were employed for optimization and structural analysis.

Main Results:

The designed Prb-Pdar complex exhibited a dissociation constant (Kd) of 130 nM, significantly higher than previous designs.
Directed evolution improved the binding affinity to 180 pM.
Crystal structures revealed that binding occurred at the designed interface, even with a 180° rotation of one partner in the evolved complex.

Conclusions:

Computational design of complementary surfaces can create high-affinity protein interfaces.
The study validates a powerful strategy for de novo protein complex design.
Unexpected structural rearrangements highlight the robustness and adaptability of designed interactions.