Simulating protein structures involved in memory formation

Our brain’s remarkable ability to form and store memories has long fascinated scientists, yet most of the microscopic mechanisms behind memory and learning processes remain a mystery. Recent research points to the importance of biochemical reactions occurring at postsynaptic densities—specialized areas where neurons connect and communicate. These tiny junctions between brain cells are now thought to be crucial sites where proteins need to organize in specific ways to facilitate learning and memory formation.

More specifically, a 2021 study revealed that memory-related proteins can bind together to form droplet-like structures at postsynaptic densities. What makes these structures particularly intriguing is their unique “droplet-inside-droplet” organization, which scientists believe may be fundamental to how our brains create lasting memories. However, understanding exactly how and why such complex protein arrangements form has remained a significant challenge in neuroscience.

Against this backdrop, a research team led by Researcher Vikas Pandey from the International Center for Brain Science (ICBS), Fujita Health University, Japan, has developed an innovative computational model that reproduces these intricate protein structures. Their paper, published online in Cell Reports on April 07, 2025, explores the mechanisms behind the formation of multilayered protein condensates. The study was co-authored by Dr. Tomohisa Hosokawa and Dr. Yasunori Hayashi from the Department of Pharmacology, Kyoto University Graduate School of Medicine, and Dr. Hidetoshi Urakubo from ICBS, Fujita Health University.

The researchers focused on four proteins found at synapses, with special attention to Ca²⁺/calmodulin-dependent protein kinase II (CaMKII)—a protein particularly abundant in postsynaptic densities. Using computational modeling techniques, they simulated how these proteins interact and organize themselves under various conditions. Their model successfully reproduced the formation of the above-mentioned “droplet-inside-droplet” structures observed in earlier experiments. Through simulations and detailed analyses of the physical forces and chemical interactions involved, the research team shed light on a process called liquid-liquid phase separation (LLPS); it involves proteins spontaneously organizing into condensates without membranes that sometimes resemble the organelles found inside cells.

Crucially, the researchers found that the distinctive “droplet-inside-droplet” structure appears as a result of competitive binding between the proteins and is significantly influenced by the shape of CaMKII, specifically its high valency (number of binding sites) and short linker length. These shape-related properties of CaMKII result in low surface tension and slow diffusion, allowing the protein condensates to remain stable for extended periods. This stability enables the sustained activation of downstream signaling pathways necessary for synaptic plasticity, which is the cellular basis for learning and memory. “Our results revealed new structure–function relationships for CaMKII as a synaptic memory unit. This is the first systematic and mechanistic study investigating the divergent structure of protein-regulated multiphase condensates,” highlights Dr. Pandey.

These findings could pave the way toward a better understanding of the possible mechanisms of memory formation in humans. However, the long-term implications of this research extend well beyond basic neuroscience.

Defects in synapse formation have been associated with numerous neurological and mental health conditions, including schizophrenia, autism spectrum disorders, Down syndrome, and Rett syndrome. “Overall, the computational model developed in this study could serve as an important platform for investigating these conditions, potentially leading to new diagnostic tools and therapeutic approaches,” explains Dr. Pandey.

Let us hope scientists continue to unravel the mysteries of how memories form at the molecular level, leading us to a more thorough comprehension of one of the brain’s most fundamental and complex functions.

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Reference

DOI: 10.1016/j.celrep.2025.115504

About Fujita Health University
Fujita Health University (FHU) is a private medical university located in Aichi, Japan. Established in 1964, it houses one of the largest university hospitals in Japan. It’s 900 member faculty provides diverse learning and research opportunities to medical students worldwide. Guided by its founding philosophy of “Our creativity for the people” Fujita Health University believes that it’s students can shape the future through creativity and innovation. FHU has earned global recognition, ranking eighth among all universities and second among private universities in Japan in the 2020 Times Higher Education (THE) World University Rankings. The university ranked fourth worldwide in the 2024 THE University Impact Rankings for contributions to the “Good Health and Well-being” SDG (Sustainable Development Goals) of the United Nations (UN). In June 2021, the university made history as the first Japanese institution to host the THE Asia Universities Summit. In 2024, Fujita Health University was awarded the Forming Japan’s Peak Research Universities (J-PEAKS) Program by the Japanese government to establish an innovative academic drug discovery ecosystem and hub of a multi-university consortium for research and education.

Website: https://www.fujita-hu.ac.jp/en/index.html

About Dr. Vikas Pandey from Fujita Health University, Japan
Dr. Vikas Pandey obtained MS and PhD degrees from the Indian Institute of Technology, Bombay, India, in 2012 and 2017, respectively. He is currently a Special Research Fellow at Fujita Health University. His research interests revolve around systems biology, computational neuroscience, nonlinear dynamics, and mathematical biology. He has published many research papers on these topics.

Funding information
This project received funding from the Core Research for Evolutional Science and Technology (CREST), the Japan Science and Technology Agency (JST) (grant no. JPMJCR20E4), JSPS KAKENHI (JP19K06885, JP24H02317 and JP20K12062), Kobayashi foundation, ISHIZUE2024 of Kyoto University, Grant-in-Aid for Scientific Research JP18H05434, JP20K21462, and JP22K21353 from MEXT, Japan; the Uehara Memorial Foundation; the Naito Foundation; Research Foundation for Opto-Science and Technology; Novartis Foundation; the Takeda Science Foundation; and HFSP Research Grant RGP0020/2019.