82
4 Concluding Remarks and Future Perspectives
are in a competition, affecting the melanin composition by determining the eumelanin/pheomelanin ratio. Since both the reactions proceed with charge redistribution, the HOMO and LUMO level of o-quinone are important factors affecting the
reactivity.
To demonstrate the competition, we showed that binding of thiols become unfavorable upon cyclization. Especially, in the case of dopaquinone, the cyclized product
dopachrome showed a significantly reduced binding energy to thiols with a highly
up-shifted LUMO level by cyclization. In contrast, RD-quinone can bind thiols even
after cyclization with a less up-shifted LUMO level by cyclization.
From an investigation on cyclization of o-quinone and substituent effects, it was
found that α-carboxylation and N-methylation enhances the nucleophilicity of the
side chain. It was pointed out that the amino lone pair electrons became more unstable
by introducing these substituents, and results in a more aggressive charge donation by
means of nucleophilic attack. In the case of RD-quinone, cyclic C−O bond formation
requires hydroxyl deprotonation (or quinonic protonation), indicating a less preference for cyclization over thiol binding. Considering several cytotoxic effects of thiol
binding reported so far, this preference for thiol binding of RD-quinone may be a
factor contributing to the cytotoxicity.
Aiming to understand the binding mechanism of cysteine to dopaquinone, the
energetic preference of cysteine thiolate ion for various possible binding sites was
investigated. As an important finding, C3−C4 bridge site but not C5 and C2 was
identified as the most stable site. Although the C6-adduct has never been reported
as the major product, our calculated results showed that the binding at C2 is not
energetically stable than at C6. Therefore, an alternative explanation other than
straightforward energetics augment is necessary. As the mechanism for the initial
step for cysteine binding, it was proposed that cysteine thiolate is initially bound
onto C3−C4 bridge, and then migrates to the adjacent sites C5 and C2. Recently, we
have proposed a mechanism of the cysteine addition reaction to form cysteinyldopa
via a thiolate-attacked intermediate at C3−C4 bridge [1].
While the classical description of atomic nuclei is sufficient for most scenarios,
certain phenomena require quantum mechanical description to fully understand the
phenomena. Hydrogen exhibits quantum mechanical phenomena compared to other
elements, as quantum mechanical features are significantly associated with low-mass
particles. From our previous studies, we have shown that quantum mechanical treatment is essential for describing the behavior of hydrogen on solid surfaces [2]. As
shown in this book, proton transfer such as protonation and deprotonation proceed
in melanin formation, and a quantum mechanical description of the nucleus is essential. Our preliminary results show that the quantum tunneling effect is considerable.
Further research will be conducted to gain a complete understanding of melanin
chemistry from the atomic nuclear and electronic world.
Melanin chemistry has been developed through multi-disciplinary collaboration.
In this book, we introduced case studies on chemical reactions in melanogenesis
based on CMD
® approach, where the electronic states of molecules are computed
from the first principles of quantum theory. From the computational studies, various
factors that control the reaction were clarified and the atomic-scale understanding
4 Concluding Remarks and Future Perspectives
are in a competition, affecting the melanin composition by determining the eumelanin/pheomelanin ratio. Since both the reactions proceed with charge redistribution, the HOMO and LUMO level of o-quinone are important factors affecting the
reactivity.
To demonstrate the competition, we showed that binding of thiols become unfavorable upon cyclization. Especially, in the case of dopaquinone, the cyclized product
dopachrome showed a significantly reduced binding energy to thiols with a highly
up-shifted LUMO level by cyclization. In contrast, RD-quinone can bind thiols even
after cyclization with a less up-shifted LUMO level by cyclization.
From an investigation on cyclization of o-quinone and substituent effects, it was
found that α-carboxylation and N-methylation enhances the nucleophilicity of the
side chain. It was pointed out that the amino lone pair electrons became more unstable
by introducing these substituents, and results in a more aggressive charge donation by
means of nucleophilic attack. In the case of RD-quinone, cyclic C−O bond formation
requires hydroxyl deprotonation (or quinonic protonation), indicating a less preference for cyclization over thiol binding. Considering several cytotoxic effects of thiol
binding reported so far, this preference for thiol binding of RD-quinone may be a
factor contributing to the cytotoxicity.
Aiming to understand the binding mechanism of cysteine to dopaquinone, the
energetic preference of cysteine thiolate ion for various possible binding sites was
investigated. As an important finding, C3−C4 bridge site but not C5 and C2 was
identified as the most stable site. Although the C6-adduct has never been reported
as the major product, our calculated results showed that the binding at C2 is not
energetically stable than at C6. Therefore, an alternative explanation other than
straightforward energetics augment is necessary. As the mechanism for the initial
step for cysteine binding, it was proposed that cysteine thiolate is initially bound
onto C3−C4 bridge, and then migrates to the adjacent sites C5 and C2. Recently, we
have proposed a mechanism of the cysteine addition reaction to form cysteinyldopa
via a thiolate-attacked intermediate at C3−C4 bridge [1].
While the classical description of atomic nuclei is sufficient for most scenarios,
certain phenomena require quantum mechanical description to fully understand the
phenomena. Hydrogen exhibits quantum mechanical phenomena compared to other
elements, as quantum mechanical features are significantly associated with low-mass
particles. From our previous studies, we have shown that quantum mechanical treatment is essential for describing the behavior of hydrogen on solid surfaces [2]. As
shown in this book, proton transfer such as protonation and deprotonation proceed
in melanin formation, and a quantum mechanical description of the nucleus is essential. Our preliminary results show that the quantum tunneling effect is considerable.
Further research will be conducted to gain a complete understanding of melanin
chemistry from the atomic nuclear and electronic world.
Melanin chemistry has been developed through multi-disciplinary collaboration.
In this book, we introduced case studies on chemical reactions in melanogenesis
based on CMD
® approach, where the electronic states of molecules are computed
from the first principles of quantum theory. From the computational studies, various
factors that control the reaction were clarified and the atomic-scale understanding