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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...

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...

Ligand Binding Sites

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...

Protein Organization

Protein Organization

Proteins are polymers of amino acid residues. They are versatile and responsible for different cellular functions, including DNA replication, molecular transport, catalysis, and structural support. Proteins have a hierarchical structure comprising at least three levels of organization: primary, secondary, and tertiary structure. Some large proteins have a quaternary structure where individual protein subunits are linked together.
The primary structure of a protein is its amino acid sequence.

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

Updated: Jun 26, 2026

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

Caveat emptor: predicting and modeling protein-DNA recognition and binding via machine-learning computational

Morgan A Esler¹, Rachel Werther¹, Lindsey A Doyle¹

¹Division of Basic Sciences, Fred Hutchinson Cancer Center, 1100 Fairview Ave. N., Seattle, WA 98109, United States.

Nucleic Acids Research

|June 25, 2026

Summary

AI tools like AlphaFold3 excel at protein structure prediction but struggle with protein-DNA interactions. This study highlights inaccuracies in predicting these complexes, warning against flawed data in future AI training.

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Last Updated: Jun 26, 2026

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

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Application of I TASSER, trRosetta, UCSF Chimera, HADDOCK server, and HEX loria for De Novo and In Silico Design of Proteins

Published on: July 8, 2025

Area of Science:

Molecular Biology
Structural Biology
Bioinformatics

Background:

Artificial intelligence (AI) tools have revolutionized molecular biology.
AlphaFold3 demonstrates high accuracy for protein structures and protein-protein complexes.
The predictive performance of AI for protein-nucleic acid interactions is less understood.

Purpose of the Study:

To review AI tools for predicting protein-DNA interactions.
To evaluate the accuracy of AlphaFold3 in modeling protein-DNA complexes.
To identify potential issues and limitations in current AI-driven predictions.

Main Methods:

Literature review of protein-DNA interaction prediction tools.
Performance analysis of AlphaFold3 using a well-defined protein-DNA system.
Examination of hybrid modeling approaches in Cryo-EM data.

Main Results:

AlphaFold3's accuracy in predicting protein-DNA contacts is not well-established.
Demonstrated challenges and inaccuracies in modeling protein-DNA interactions with current AI.
Identified a potential for inaccurate learning cycles with hybrid models.

Conclusions:

Current AI tools, including AlphaFold3, require careful validation for protein-DNA interaction predictions.
The integration of unrefined hybrid models may perpetuate inaccuracies in AI training datasets.
Further development and rigorous testing are needed for reliable AI-based prediction of protein-nucleic acid complexes.