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The protonation status of compound II in myoglobin, studied by a combination of experimental data and quantum chemical calculations: quantum refinement.

ABSTRACT: Treatment of met-myoglobin (FeIII) with H2O2 gives rise to ferryl myoglobin, which is closely related to compound II in peroxidases. Experimental studies have given conflicting results for this species. In particular, crystallographic and extended x-ray absorption fine-structure data have shown either a short (approximately 170 pm) or a longer (approximately 190 pm) Fe-O bond, indicating either a double or a single bond. We here present a combined experimental and theoretical investigation of this species. In particular, we use quantum refinement to re-refine a crystal structure with a long bond, using 12 possible states of the active site. The states differ in the formal oxidation state of the iron ion and in the protonation of the oxygen ligand (O2-, OH-, or H2O) and the distal histidine residue (with a proton on Ndelta1, Nepsilon2, or on both atoms). Quantum refinement is essentially standard crystallographic refinement, where the molecular-mechanics potential, normally used to supplement the experimental data, is replaced by a quantum chemical calculation. Thereby, we obtain an accurate description of the active site in all the different protonation and oxidation states, and we can determine which of the 12 structures fit the experimental data best by comparing the crystallographic R-factors, electron-density maps, strain energies, and deviation from the ideal structure. The results indicate that FeIII OH- and FeIV OH- fit the experimental data almost equally well. These two states are appreciably better than the standard model of compound II, FeIV O2-. Combined with the available spectroscopic data, this indicates that compound II in myoglobin is protonated and is best described as FeIV OH-. It accepts a hydrogen bond from the distal His, which may be protonated at low pH.

SUBMITTER: Nilsson K

PROVIDER: S-EPMC1304810 | biostudies-literature | 2004 Nov

REPOSITORIES: biostudies-literature

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The protonation status of compound II in myoglobin, studied by a combination of experimental data and quantum chemical calculations: quantum refinement.

Nilsson Kristina K Hersleth Hans-Petter HP Rod Thomas H TH Andersson K Kristoffer KK Ryde Ulf U

Biophysical journal 20040831 5

Treatment of met-myoglobin (FeIII) with H2O2 gives rise to ferryl myoglobin, which is closely related to compound II in peroxidases. Experimental studies have given conflicting results for this species. In particular, crystallographic and extended x-ray absorption fine-structure data have shown either a short (approximately 170 pm) or a longer (approximately 190 pm) Fe-O bond, indicating either a double or a single bond. We here present a combined experimental and theoretical investigation of th ...[more]

PMID: 15339813

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Project description:The accurate prediction of protein chemical shifts using a quantum mechanics (QM)-based method has been the subject of intense research for more than 20 years but so far empirical methods for chemical shift prediction have proven more accurate. In this paper we show that a QM-based predictor of a protein backbone and CB chemical shifts (ProCS15, PeerJ, 2016, 3, e1344) is of comparable accuracy to empirical chemical shift predictors after chemical shift-based structural refinement that removes small structural errors. We present a method by which quantum chemistry based predictions of isotropic chemical shielding values (ProCS15) can be used to refine protein structures using Markov Chain Monte Carlo (MCMC) simulations, relating the chemical shielding values to the experimental chemical shifts probabilistically. Two kinds of MCMC structural refinement simulations were performed using force field geometry optimized X-ray structures as starting points: simulated annealing of the starting structure and constant temperature MCMC simulation followed by simulated annealing of a representative ensemble structure. Annealing of the CHARMM structure changes the CA-RMSD by an average of 0.4 Å but lowers the chemical shift RMSD by 1.0 and 0.7 ppm for CA and N. Conformational averaging has a relatively small effect (0.1-0.2 ppm) on the overall agreement with carbon chemical shifts but lowers the error for nitrogen chemical shifts by 0.4 ppm. If an amino acid specific offset is included the ProCS15 predicted chemical shifts have RMSD values relative to experiments that are comparable to popular empirical chemical shift predictors. The annealed representative ensemble structures differ in CA-RMSD relative to the initial structures by an average of 2.0 Å, with >2.0 Å difference for six proteins. In four of the cases, the largest structural differences arise in structurally flexible regions of the protein as determined by NMR, and in the remaining two cases, the large structural change may be due to force field deficiencies. The overall accuracy of the empirical methods are slightly improved by annealing the CHARMM structure with ProCS15, which may suggest that the minor structural changes introduced by ProCS15-based annealing improves the accuracy of the protein structures. Having established that QM-based chemical shift prediction can deliver the same accuracy as empirical shift predictors we hope this can help increase the accuracy of related approaches such as QM/MM or linear scaling approaches or interpreting protein structural dynamics from QM-derived chemical shift.

Dataset Information

The protonation status of compound II in myoglobin, studied by a combination of experimental data and quantum chemical calculations: quantum refinement.

Publications

The protonation status of compound II in myoglobin, studied by a combination of experimental data and quantum chemical calculations: quantum refinement.

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