Computational analysis of the tryptophan cation radical energetics in peroxidase Compound $\mathrm{I}$

Poulos, Thomas L.; Kim, Jenny S.; Murarka, Vidhi C.

doi:10.1007/s00775-022-01925-8

Computational analysis of the tryptophan cation radical energetics in peroxidase Compound $$\mathrm{I}$$

Journal Article · Fri Jan 21 00:00:00 EST 2022 · JBIC Journal of Biological Inorganic Chemistry

DOI:https://doi.org/10.1007/s00775-022-01925-8· OSTI ID:1903970

^[1]; Kim, Jenny S. ^[2]; Murarka, Vidhi C. ^[2]

University of California, Irvine, CA (United States); OSTI
University of California, Irvine, CA (United States)

Three well-characterized heme peroxidases (cytochrome c peroxidase = CCP, ascorbate peroxidase = APX, and Leishmania major peroxidase = LMP) all have a Trp residue tucked under the heme stacked against the proximal His heme ligand. The reaction of peroxidases with H₂O₂ to give Compound I results in the oxidation of this Trp to a cationic radical in CCP and LMP but not in APX. Considerable experimental data indicate that the local electrostatic environment controls whether this Trp or the porphyrin is oxidized in Compound I. Attempts have been made to place the differences between these peroxidases on a quantitative basis using computational methods. These efforts have been somewhat limited by the approximations required owing to the computational cost of using fully solvated atomistic models with well-developed forcefields. This now has changed with available GPU computing power and the associated development of software. Here we employ thermodynamic integration and multistate Bennett acceptance ratio methods to help fine-tune our understanding on the energetic differences in Trp radical stabilization in all three peroxidases. These results indicate that the local solvent structure near the redox active Trp plays a significant role in stabilization of the cationic Trp radical.

View Accepted Manuscript (DOE)

Research Organization:: SLAC National Accelerator Laboratory (SLAC), Menlo Park, CA (United States). Stanford Synchrotron Radiation Lightsource (SSRL); University of California, Irvine, CA (United States)

Sponsoring Organization:: National Institutes of Health (NIH); USDOE Office of Science (SC), Basic Energy Sciences (BES); USDOE Office of Science (SC), Biological and Environmental Research (BER)

Grant/Contract Number:: AC02-76SF00515

OSTI ID:: 1903970

Journal Information:: JBIC Journal of Biological Inorganic Chemistry, Journal Name: JBIC Journal of Biological Inorganic Chemistry Journal Issue: 2 Vol. 27; ISSN 0949-8257

Publisher:: SpringerCopyright Statement

Country of Publication:: United States

Language:: English

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37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY
59 BASIC BIOLOGICAL SCIENCES
computational biology
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heme peroxidases

Computational analysis of the tryptophan cation radical energetics in peroxidase Compound $$\mathrm{I}$$

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