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

Literature Information

Publication Date 2018-08-03
DOI 10.1039/C8CP02939C
Impact Factor 3.676
Authors

Wook Lee, Inkoo Kim, Young Min Rhee


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Abstract

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.

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Physical Chemistry Chemical Physics

Physical Chemistry Chemical Physics
CiteScore: 5.5
Self-citation Rate: 10.3%
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Physical Chemistry Chemical Physics (PCCP) is an international journal co-owned by 19 physical chemistry and physics societies from around the world. This journal publishes original, cutting-edge research in physical chemistry, chemical physics and biophysical chemistry. To be suitable for publication in PCCP, articles must include significant innovation and/or insight into physical chemistry; this is the most important criterion that reviewers and Editors will judge against when evaluating submissions. The journal has a broad scope and welcomes contributions spanning experiment, theory, computation and data science. Topical coverage includes spectroscopy, dynamics, kinetics, statistical mechanics, thermodynamics, electrochemistry, catalysis, surface science, quantum mechanics, quantum computing and machine learning. Interdisciplinary research areas such as polymers and soft matter, materials, nanoscience, energy, surfaces/interfaces, and biophysical chemistry are welcomed if they demonstrate significant innovation and/or insight into physical chemistry. Joined experimental/theoretical studies are particularly appreciated when complementary and based on up-to-date approaches.

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