A proton transfer network that generates deprotonated tyrosine is a key to producing reactive oxygen species in phototoxic KillerRed protein

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KillerRed is the first genetically encoded photosensitizer that can induce cytotoxicity upon light exposure. Nevertheless, its phototoxicity is still lower than that of chemical photosensitizers, and the efforts to further develop KillerRed variants with enhanced phototoxicity have been impeded because the mechanism by which it generates cytotoxic reactive oxygen species (ROS) has remained elusive. To shed light on this issue, we employ quantum mechanics/molecular mechanics (QM/MM) modeling with statistical free energy analysis to examine the photo-induced electron transfer reaction occurring in KillerRed. We identify a deprotonated tyrosine residue (Tyr110) as an electron donor and further show that adjacent glutamate and serine residues play essential roles in deprotonating Tyr110. We also show that water mediation is important in the proton transfer and that protein fluctuations importantly govern the fate of the excited system. We provide clues about why KillerRed can only exhibit a low ROS yield and suggest future directions of mutagenesis toward an enhanced phototoxicity.
Publisher
ROYAL SOC CHEMISTRY
Issue Date
2018-09
Language
English
Article Type
Article
Keywords

COUPLED ELECTRON-TRANSFER; GREEN FLUORESCENT PROTEIN; STRUCTURAL BASIS; THYMINE DIMERIZATION; EXCITED-STATES; ACTIVE-SITE; BASIS-SETS; DENSITY; PHOTOSENSITIZER; MECHANISMS

Citation

PHYSICAL CHEMISTRY CHEMICAL PHYSICS, v.20, no.34, pp.22342 - 22350

ISSN
1463-9076
DOI
10.1039/c8cp02939c
URI
http://hdl.handle.net/10203/247147
Appears in Collection
CH-Journal Papers(저널논문)
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