Computing Proton-Coupled Redox Potentials of Fluorotyrosines in a Protein Environment

Clorice R. Reinhardt, Raquel Sequeira, Cecilia Tommos, Sharon Hammes-Schiffer

Research output: Contribution to journalArticlepeer-review

7 Scopus citations

Abstract

The oxidation of tyrosine to form the neutral tyrosine radical via proton-coupled electron transfer is essential for a wide range of biological processes. The precise measurement of the proton-coupled redox potentials of tyrosine (Y) in complex protein environments is challenging mainly because of the highly oxidizing and reactive nature of the radical state. Herein, a computational strategy is presented for predicting proton-coupled redox potentials in a protein environment. In this strategy, both the reduced Y-OH and oxidized Y-O• forms of tyrosine are sampled with molecular dynamics using a molecular mechanical force field. For a large number of conformations, a quantum mechanical/molecular mechanical (QM/MM) electrostatic embedding scheme is used to compute the free-energy differences between the reduced and oxidized forms, including the zero-point energy and entropic contributions as well as the impact of the protein electrostatic environment. This strategy is applied to a series of fluorinated tyrosine derivatives embedded in a de novo α-helical protein denoted as α3Y. The force fields for both the reduced and oxidized forms of these noncanonical fluorinated tyrosine residues are parameterized for general use. The calculated relative proton-coupled redox potentials agree with experimentally measured values with a mean unsigned error of 24 mV. Analysis of the simulations illustrates that hydrogen-bonding interactions between tyrosine and water increase the redox potentials by ∼100-250 mV, with significant variations because of the fluctuating protein environment. This QM/MM approach enables the calculation of proton-coupled redox potentials of tyrosine and other residues such as tryptophan in a variety of protein systems.

Original languageEnglish (US)
Pages (from-to)128-136
Number of pages9
JournalJournal of Physical Chemistry B
Volume125
Issue number1
DOIs
StatePublished - Jan 14 2021
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Physical and Theoretical Chemistry
  • Surfaces, Coatings and Films
  • Materials Chemistry

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