Calculation of Reduction Potential and p K _a

Abstract

Three methods, quantum mechanical and molecular mechanical polarizable continuum model (QM/MM/PCM), QM/PCM, and empirical, were developed and applied to calculate protein reduction potential ( E 0 ) and p K a values. In the QM/MM/PCM calculation of Lys55 p K a of turkey ovomucoid third domain (OMTKY3), the MP2/6‐31 + G(2d,p) method was used to describe the QM region consisting of ∼45 atoms; the rest of the protein was modeled either with ab initio‐derived electric multipole points or atomic charges from standard force field methods; and the aqueous solvation effect was described with the polarizable continuum model (PCM). The calculated Lys55 p K a values are in good agreement with experiments. QM/PCM methods were used to calculate p K a values of various proteins and the E 0 of type‐1 Cu centers. For solvent‐exposed p K a sites, QM/PCM (MP2/6‐31 + G(2d,p) for ∼100 atoms, PCM with dielectric = 78.39 for aqueous solution) methods can often reproduce experimental p K a values. For type‐1 Cu E 0 , because of protein burial, the desolvation effect becomes significant: it was found that Cu‐ligand interactions and desolvation can potentially change the E 0 by ∼300 and ∼400 mV, respectively, using the CPCM/B3LYP/6‐311++G(2df,p) method and model molecules of ∼100 atoms. An empirical method, PROPKA, was developed for protein p K a calculation and analysis, which is able to calculate the p K a values of a protein within ∼1 s.

Redox Potentials of Disulfide Bonds in LOXL2 Studied by Nonequilibrium Alchemical Simulation

“…To determine the redox potential of the disulfide bond in protein, maleimide-biotin (MPB) labeling of free cysteine thiols and Western blot densitometry are suitable experimental ways ( Liang et al, 2011 ; Cook et al, 2013 ; Chiu et al, 2014 ), and differential cysteine labeling, tandem mass spectrometry, and the structural character of the disulfide bond are also used as references in determining the function role of the disulfide bond ( Bekendam et al, 2016 ; Read et al, 2017 ; Butera et al, 2018 ). Because of the fact that redox potential is very sensitive to the structure of protein, the pKa value of sulfide, the protein’s electrostatic environment, etc., a stable measurement method for redox potential is demanding ( Quan et al, 2007 ; Jensen and Li, 2009 ; Li et al, 2015 ). Redox potentials can also be calculated by theoretical methods, e.g., molecular dynamics (MD) simulations ( Pohorille et al, 2010 ; Dellago and Hummer, 2013 ; Li et al, 2015 ) and quantum mechanics and molecular mechanics (QM/MM) approaches ( Blumberger, 2008 ; Kamerlin et al, 2009 ; Zeng et al, 2009 ; Baldus and Gräter, 2012 ).…”

Exploring Coupled Redox and pH Processes with a Force-Field-Based Approach: Applications to Five Different Systems

“…Problems related to redox processes are commonly theoretically investigated using QM [7][8][9] or QM/MM [10][11][12][13] approaches. In a previous publication 14 we have presented the implementation of a fully force field-based approach in AMBER that allows the execution of constant pH and constant redox potential molecular dynamics (C(pH,E)MD).…”