Exploring peptide agglutination to improve drug and material solutions

Chinese scientists have studied how short peptide chains aggregate to deepen our understanding of the process crucial for drug stability and materials development.

Their study, published in JACS Auprovides valuable insights into how short proteins called peptides interact, fold, and function. These findings have important implications for medicine, materials science, and biotechnology.

Peptides are short chains of amino acids that play essential roles in the body by building structures, speeding up chemical reactions, and supporting our immune system. The specific function of a protein is determined by how its amino acids interact with each other and aggregate into a three-dimensional structure.

The research team used molecular dynamics simulations along with advanced AI techniques, including deep learning models like Transformer Regression Networks, to predict how various four- or five-amino acid peptides (tetrapeptides and pentapeptides, respectively) would aggregate based on their amino acid sequence.

By analyzing 160,000 tetrapeptides and 3.2 million pentapeptides, they discovered that certain amino acids, particularly aromatic ones such as tryptophan, phenylalanine and tyrosine, significantly enhance aggregation, especially when they are located towards one end (the C-terminus) of the peptide chain.

This is likely because aromatic amino acids have ring-like structures that attract each other through their electron clouds, normally called “π-π” interactions, which helps them clump together. In contrast, hydrophilic amino acids, such as aspartic acid and glutamic acid, inhibit aggregation due to the strong interaction with water molecules that prevents the peptides from sticking together.

The study also showed that changing the amino acid sequence affects aggregation. For example, adding aromatic amino acids to the end of the peptide chain increases aggregation, while placing negatively charged amino acids at the beginning reduces it. The team also found that peptides clump together in different ways depending on the types and positions of their amino acids.

“Charged amino acids typically cause peptides to form long, thread-like structures, while those that avoid water tend to create round, ball-like clusters,” said Dr. Wenbin Li, assistant professor at Westlake University and corresponding author of the study.

“We also found that by understanding how tetrapeptides stick together, we can predict how pentapeptides will behave, which makes it easier to predict how longer peptides will stick together.”

The results provide important guidelines for predicting and managing how peptides aggregate.

“This knowledge could help create new materials, design more stable drugs and drug delivery systems, and understand diseases related to peptide aggregation, such as Alzheimer’s disease, where clumped amyloid beta peptides form damaging plaques in the brain,” said Dr. Jiaqi Wang, Assistant Professor at Xi’an Jiaotong-Liverpool University (XJTLU) and first author of the study.

“It can also improve biotechnology, such as semiconductors, biosensors and diagnostics, by ensuring that these tools operate accurately and consistently.

“By providing new insights into peptide aggregation, this research is expected to advance biochemistry, materials science, and computational biology. It also demonstrates the integration of AI into scientific discovery. These advances could lead to breakthroughs in medical treatments, environmentally friendly products, and innovative technologies.”