Researchers Discover Key Mechanism Behind Protein Aggregation Inhibition by Zwitterionic Polymers

Ishikawa, Japan – Proteins play essential roles in countless biological processes and are often referred to as the engines of cellular function. They are formed by chains of amino acids that fold into three-dimensional shapes—a process known as protein folding. For a protein to function correctly, it must adopt its unique three-dimensional structure, also known as its 'native state.' However, under stressful conditions or exposure to harmful agents, proteins may misfold and clump together, forming aggregates that disrupt their natural function.

Protein misfolding is a known contributor to several debilitating diseases, such as Alzheimer’s, Huntington’s, and Parkinson’s. Additionally, protein aggregation also affects the safety and effectiveness of protein-based therapeutics. Therefore, there is a growing need to explore methods that can prevent misfolding and promote protein stability.

While some polymers have recently been noted for their ability to stabilize proteins, the precise mechanism by which they accomplish this, along with the role of hydrophobic (water-repelling) interactions, remains elusive.

A team of scientists, led by Professor Kazuaki Matsumura from the Japan Advanced Institute of Science and Technology (JAIST), alongside former Assistant Professor Robin Rajan, research fellow Dr. Dandan Zhao from JAIST, and Assistant Professor Tadaomi Furuta from the Tokyo Institute of Technology, sought to shed light on the mechanism behind protein aggregation inhibition by sulfobetaine (SPB). Their study, recently published in Cell Reports Physical Science, also probed the role hydrophobic interactions play in protein stability, aiming to broaden the current understanding of protein-polymer dynamics.

According to Prof. Matsumura, “In an earlier study on polysulfobetaines (PSPBs)—a class of zwitterionic polymers containing both positive and negative charges—we identified their significant role in preventing protein aggregation. However, the specific contributions of hydrophobicity had yet to be explored.”

The research team synthesized PSPBs with varying molecular weights and systematically introduced different hydrophobic monomers and alkyl chains using a technique known as reversible addition-fragmentation chain transfer polymerization. They then examined how these polymers impacted protein stability and studied the intricate interactions between the polymers and the proteins using various physicochemical methods.

The findings indicated that the polymers helped to inhibit protein aggregation by interfering with critical steps in the aggregation process. Both hydrophobicity and the molecular dimensions of the polymers appeared to enhance their protein-stabilizing capabilities. Increased levels of these factors led to more robust, reversible interactions between SPB and proteins. Prof. Matsumura elaborates, “These polymers act like temporary shields, effectively disrupting the pathways that lead to aggregation.” Their experiments also revealed that after stress was removed, the proteins could refold into their native states, suggesting partial recovery of their regular functions.

By providing crucial insights into the molecular processes that suppress protein aggregation, this study could significantly impact next-generation therapeutic strategies aimed at delaying or preventing disease states linked to protein misfolding. It may also contribute to the safer development and long-term stability of protein-based drugs.

Prof. Matsumura concludes, “In the next 5 to 10 years, this research has the potential to yield innovative therapeutic approaches for diseases associated with protein misfolding. These advancements could vastly improve patient care while providing more stable and cost-effective protein therapies, benefiting the pharmaceutical industry and healthcare professionals alike.”

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Reference

Title of original paper:
Molecular mechanism of protein aggregation inhibition with sulfobetaine polymers and their hydrophobic derivatives

Authors:
Robin Rajan*, Tadaomi Furuta, Dandan Zhao, Kazuaki Matsumura*

Journal:
Cell Reports Physical Science

DOI:
10.1016/j.xcrp.2024.102012

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About Japan Advanced Institute of Science and Technology (JAIST), Japan

Established in 1990 in Ishikawa Prefecture, the Japan Advanced Institute of Science and Technology (JAIST) is Japan’s first independent national graduate institution. Over the past 30 years, JAIST has consistently ranked among Japan's top universities. With a focus on fostering future leaders through an innovative curriculum that emphasizes coursework-based training, JAIST supports cutting-edge research. Around 40% of its graduates come from international backgrounds. Additionally, JAIST works closely with industries and academic institutions both locally and globally to promote collaborative research.

About Professor Kazuaki Matsumura

Dr. Kazuaki Matsumura is a Professor at JAIST with over 170 published papers. His work focuses on biomaterials, biomedical engineering, and medical systems. With 23 years of research experience, he currently serves as the Director of the Research Center for Exponential Biomedical DX as well as Director of the Materials Chemistry Frontiers Research Area at JAIST. Dr. Matsumura received his Ph.D. in Engineering from Kyoto University in 2004.

Funding Information:
This research was supported by grants from the Japan Society for the Promotion of Science (KAKENHI, Grants 20K20197, 23K17211, 20H04532, and 21H05516) and the JST Adaptable and Seamless Technology Transfer Program through Target-driven R&D (A-STEP, JPMJTR20UN).

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Journal

Cell Reports Physical Science

DOI

10.1016/j.xcrp.2024.102012

Article Title

Molecular mechanism of protein aggregation inhibition with sulfobetaine polymers and their hydrophobic derivatives

Article Publication Date

30-May-2024