●Mechanistic studies on protein aggregation : Protein functions with a defined structure. Once it aggregates, it may affect and denature the structure of other natural proteins. For example, protein aggregation is observed for amyloid beta peptides in Alzheimer’s disease and prion proteins in Creutzfeldt-Jakob and mad cow diseases. These diseases are called ‘protein aggregation diseases’ and have gained much attention. However, the aggregation mechanism of proteins is still not known well. We are studying the aggregation processes of proteins.



●Construction of new supramolecules with proteins : Supramolecular chemistry has been studied extensively after many pioneer works reported by Jean-Marie Lehn in the 70’s and is now one of the major topics in science. Supramolecule is a well-defined system with molecules connected by weak interactions, and it creates a new function which a single molecule cannot generate. Recently, it is desired to construct a more detailed system, and organization of biomolecules at a higher order has gained interest. We are constructing new supramolecules using proteins.



●Development of new photoactive proteins : Protein molecules form a well-defined three-dimensional structure to function, although they are very large (molecular weight is more than a few thousands). Therefore, control of its function becomes possible if we control the three-dimensional structure of the protein. We are developing new methods to control the three-dimensional protein structures and their supramolecular structures. For example, we have photocontrolled formation of the protein three-dimensional structure and succeeded in observing its structural formation (Fig. 1). We are now developing new techniques to practically apply this method.



Fig. 1 Photocontrol of protein structural formation.
(J. Am. Chem. Soc., 2006)



●Elucidation of functional mechanisms of proteins : Biomolecules function much more effectively than we can control the reactions at experimental levels. We have been studying the reaction mechanisms of proteins using various spectroscopic techniques, including FT-IR, resonance Raman, stopped flow, flash photolysis, etc. For example, we have shown the active site structural difference between the active and inactive forms of [NiFe]hydrogenase. We are also studying the oxygen binding mechanisms of copper-containing proteins (Fig. 2).


Fig. 2 Schematic view of dioxygen binding to an enzyme.
(J. Am. Chem. Soc., 2005)



●Development of photoactive metallocomplexes : DNA cleavage by metal complexes has been actively studied to design artificial metallonucleases. For this purpose, many dinuclear metal complexes have been shown to be effective, in which the metal ion centers could exhibit cooperation for DNA cleavage. We have connected two metallocomplexes with a photoisomerizable azobeneze and have succeeded to reversibly photocontrol the on-off of the DNA cleavage activity (Fig. 3). We are trying to improve the DNA cleavage activity, as well as to develop new photoactive materials based on metallocomplexes.


Fig. 3 Photoregulation of DNA cleavage.
(Inorg. Chem., 2008)



●Construction of Functional Biomolecules Based on Protein Chemical Modification and Genetic Mutation : We have attempted to construct "Artificial Biomolecules" with non-natural unique functions by organic/coordination chemistry. Furthermore, the combination of genetic mutation and synthetic approach is introduced to construct such biomolecules as a complementary strategy, which helps the development of new design methodology for creating artificial biomolecules.



●Clarification of Action Mechanism of Bioactive Small Molecules from the Viewpoint of Medicinal Chemistry : The mechanisms of some bioactive small molecules for medicinal demands (suppression of cancer etc.) are still the research targets in medicinal chemistry. We have attempted to clarify the mechanism of such bioactive molecules from the aspects of bioreaction chemistrty and to develop more effective molecules for medicinal demands.