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Related Concept Videos

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...
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...
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...
Protein Networks02:26

Protein Networks

An organism can have thousands of different proteins, and these proteins must cooperate to ensure the health of an organism. Proteins bind to other proteins and form complexes to carry out their functions. Many proteins interact with multiple other proteins creating a complex network of protein interactions.
These interactions can be represented through maps depicting protein-protein interaction networks, represented as nodes and edges. Nodes are circles that are representative of a protein,...
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 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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Related Experiment Video

Updated: May 7, 2026

Computational Prediction of Amino Acid Preferences of Potentially Multispecific Peptide-Binding Domains Involved in Protein-Protein Interactions
06:50

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

Published on: January 26, 2024

Predicting affinity- and specificity-enhancing mutations at protein-protein interfaces.

Oz Sharabi1, Jason Shirian, Julia M Shifman

  • 1*Department of Biological Chemistry, The Alexander Silberman Institute of Life Sciences, Hebrew University of Jerusalem, Jerusalem 91904, Israel.

Biochemical Society Transactions
|September 25, 2013
PubMed
Summary
This summary is machine-generated.

We developed a computational method to predict changes in protein-protein interaction (PPI) binding energy due to mutations. This tool aids in designing potent and specific PPI inhibitors for drug discovery and synthetic biology.

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Area of Science:

  • Biochemistry
  • Computational Biology
  • Drug Design

Background:

  • Protein-protein interactions (PPIs) are crucial for biological processes.
  • Current methods for manipulating PPIs lack mechanistic insight.
  • Understanding binding interfaces is key for applications like drug design.

Purpose of the Study:

  • To develop and validate a computational method for predicting binding free energy changes upon mutation in PPIs.
  • To enable deeper understanding of molecular forces governing binding interactions.
  • To facilitate computational scanning of binding interfaces for sequence optimality analysis.

Main Methods:

  • Developed a computational protocol to predict changes in binding free energy due to mutations.
  • Validated the method using two biological systems: AChE-Fas and TIMP-2-MMP14 complexes.
  • Performed computational saturated mutagenesis and interface scanning.

Main Results:

  • For the high-affinity AChE-Fas complex, the interface was found to be near-optimal, with few predicted affinity-enhancing mutations.
  • For the medium-affinity TIMP-2-MMP14 complex, the interface was non-optimal, with multiple predicted stabilizing mutations.
  • Experimental validation confirmed computational predictions, identifying numerous affinity- and specificity-enhancing mutations.

Conclusions:

  • The computational protocol effectively predicts mutations that enhance binding affinity and specificity in PPIs.
  • This method significantly aids in the discovery of mutations for designing potent and specific PPI inhibitors.
  • The approach is broadly applicable for engineering any PPI for therapeutic or synthetic biology purposes.