Professor Naoki Sugimoto has been interested in studying the physicochemical behaviors of nucleic acids. Nucleic acids form not only the canonical double helix (duplex), but also non-double helix structures such as a triplex, a G-quadruplex, and an i-motif. The formation of these non-double helix structures depends on the surrounding conditions. The intracellular environment is a crowded one, in which a wide variety of molecules coexist. Under molecular crowding environments, the non-double helix nucleic acids are very stable. The functions and structures of these nucleic acids in cells have been optimized in the crowded environments. Professor Sugimoto carried out his research under the unique hypothesis that molecular crowding in cells may play an important role in the reactions of functionalized biomolecules. During his research, he discovered a novel regulation mechanism of non-double helix structures in gene expression. Based on the results of his work, he developed a novel method to control gene expression of non-double helix nucleic acids, leading to new insights into the chemistry of nucleic acids. His major achievements are summarized below.
1. Quantification of the stability of non-double helix nucleic acids in molecular crowding
Under crowded conditions, the physical properties of crowded solutions, such as osmotic pressure, viscosity, and dielectric constant, differ from those of diluted solutions. These changes under molecular crowding conditions affect the stability and structure of nucleic acids.
Professor Sugimoto found, for example, that the formation of nucleic acid structures accompanied the formation of a hydrogen-bonding network of water surrounding the nucleic acid surface, meaning that the formation of the water network was highly sensitive to the water activity of the solution. The formation of structures such as a triplex, a G-quadruplex, and an i-motif, accompanied by the release of water, favored the molecular crowding conditions, because the water activity was decreased in these conditions. In order to better understand the structure and stability of nucleic acids, he developed a database of the behavior of nucleic acids in response to molecular crowding conditions. According to the database, new nucleic acid structures were revealed increasingly. For example, he found that the telomere sequence involved in cell carcinogenesis was stable, with the G-quadruplexes stabilizing in a daisy chain.
2. Elucidation of the functions of non-double helix nucleic acids and the development of their control methods
Based on his research on non-double helix nucleic acids in molecular crowding, Professor Sugimoto hypothesized that non-canonical structures may regulate gene expression. He also investigated the formation of non-double helix nucleic acids in responsive to different molecular environments and systemically analyzed the functions of non-double helix nucleic acids in vitro and in cells. His research revealed that the non-double helix nucleic acids played a key role in regulating gene expression. For example, the formation of very stable G-quadruplexes in the process of transcription, translation, and replication changed the amount of products and reaction rates during these biological reactions. Furthermore, he also demonstrated that these biological reactions could be suppressed or promoted by controlling the formation of non-double helix nucleic acids.
Until now, gene expression has been considered to be exclusively controlled by the DNA sequence (Sequence Code). However, his results revealed for the first time, a novel mechanism for regulating gene expression, based on the diversity of higher-order structures of nucleic acids (Dimensional Code).
3. Development of functional materials utilizing non-double helix nucleic acids
Professor Sugimoto also applied the research technologies described above to develop functional materials from nucleic acids. For example, he found that the functions of RNAs (riboswitches, ribozymes, etc.) could be controlled by molecular crowding environments. Using new artificial nucleic acids and small molecules that stabilize or induce the non-double helix, he developed new materials and technologies to suppress replication and translation, and finally to inhibit the amplification of HIV. Moreover, by utilizing the property wherein the G-quadruplex topology changes in an environment-dependent manner, he developed DNA sensors to measure the intracellular molecular crowding environment. Based on the acquired cell information, he obtained interaction parameters that could predict the structure and stability of nucleic acids in the cell. These interaction parameters have been effectively used worldwide by researchers to predict the structure and stability of nucleic acids.
Thus, Professor Sugimoto quantitatively elucidated the structure and stability of non-double helix nucleic acids that change in response to the molecular environment and used the obtained quantitative biophysical parameters as a design guideline for functional materials. These achievements have made him a recognized pioneer in an innovative research area of chemistry related to the study of non-double helix nucleic acids in molecular crowding environments, both in Japan and overseas. Furthermore, he has significantly contributed not only to the field of nucleic acid chemistry, but also to other research fields such as medicine, engineering, and agriculture. Therefore, his achievement has been recognized as worthy of the Chemical Society of Japan (CSJ) Award.