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 language | English (US) |
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Pages (from-to) | 128-136 |
Number of pages | 9 |
Journal | Journal of Physical Chemistry B |
Volume | 125 |
Issue number | 1 |
DOIs | |
State | Published - Jan 14 2021 |
Externally published | Yes |
All Science Journal Classification (ASJC) codes
- Physical and Theoretical Chemistry
- Surfaces, Coatings and Films
- Materials Chemistry