Dataset Information

Performance of Protein-Ligand Force Fields for the Flavodoxin-Flavin Mononucleotide System.

ABSTRACT: The ability to accurately perform molecular dynamics and free energy perturbation calculations for protein-ligand systems is of broad interest to the biophysical and pharmaceutical sciences. In this work, several popular force fields are evaluated for reproducing experimental properties of the flavodoxin/flavin mononucleotide system. Calculated (3)J couplings from molecular dynamics simulations probing ? and ?1 dihedral angles are compared to over 1000 experimental measurements. Free energy perturbation calculations were also executed between different protein mutants for comparison with experimental data for relative free energies of binding. Newer versions of popular protein force fields reproduced (3)J backbone and side chain couplings with good accuracy, with RMSD values near or below one hertz in most cases. OPLS-AA/M paired with CM5 charges for the ligand performed particularly well, both for the (3)J couplings and FEP results, with a mean unsigned error for relative free energies of binding of 0.36 kcal/mol.

SUBMITTER: Robertson MJ

PROVIDER: S-EPMC5813475 | biostudies-literature | 2016 Aug

REPOSITORIES: biostudies-literature

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Publications

Performance of Protein-Ligand Force Fields for the Flavodoxin-Flavin Mononucleotide System.

Robertson Michael J MJ Tirado-Rives Julian J Jorgensen William L WL

The journal of physical chemistry letters 20160726 15

The ability to accurately perform molecular dynamics and free energy perturbation calculations for protein-ligand systems is of broad interest to the biophysical and pharmaceutical sciences. In this work, several popular force fields are evaluated for reproducing experimental properties of the flavodoxin/flavin mononucleotide system. Calculated (3)J couplings from molecular dynamics simulations probing φ and χ1 dihedral angles are compared to over 1000 experimental measurements. Free energy pert ...[more]

PMID: 27441982

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Project description:Soil bacteria can detoxify Cr(VI) ions by reduction. Within the last 2 decades, numerous reports of chromate reductase enzymes have been published. These reports describe catalytic reduction of chromate ions by specific enzymes. These enzymes each have sequence similarity to known redox-active flavoproteins. We investigated the enzyme NfoR from Staphylococcus aureus, which was reported to be upregulated in chromate-rich soils and to have chromate reductase activity (H. Han, Z. Ling, T. Zhou, R. Xu, et al., Sci Rep 7:15481, 2017, https://doi.org/10.1038/s41598-017-15588-y). We show that NfoR has structural similarity to known flavin mononucleotide (FMN) reductases and reduces FMN as a substrate. NfoR binds FMN with a dissociation constant of 0.4 μM. The enzyme then binds NADPH with a dissociation constant of 140 μM and reduces the flavin at a rate of 1,350 s-1 Turnover of the enzyme is apparently limited by the rate of product release that occurs, with a net rate constant of 0.45 s-1 The rate of product release limits the rate of observed chromate reduction, so the net rate of chromate reduction by NfoR is orders of magnitude lower than when this process occurs in solution. We propose that NfoR is an FMN reductase and that the criterion required to define chromate reduction as enzymatic has not been met. That NfoR expression is increased in the presence of chromate suggests that the survival adaption was to increase the net rate of chromate reduction by facile, adventitious redox processes.IMPORTANCE Chromate is a toxic by-product of multiple industrial processes. Chromate reduction is an important biological activity that ameliorates Cr(VI) toxicity. Numerous researchers have identified chromate reductase activity by observing chromate reduction. However, all identified chromate reductase enzymes have flavin as a cofactor or use a flavin as a substrate. We show here that NfoR, an enzyme claimed to be a chromate reductase, is in fact an FMN reductase. In addition, we show that reduction of a flavin is a viable way to transfer electrons to chromate but that it is unlikely to be the native function of enzymes. We propose that upregulation of a redox-active flavoprotein is a viable means to detoxify chromate that relies on adventitious reduction that is not catalyzed.

Dataset Information

Performance of Protein-Ligand Force Fields for the Flavodoxin-Flavin Mononucleotide System.

Publications

Performance of Protein-Ligand Force Fields for the Flavodoxin-Flavin Mononucleotide System.

Similar Datasets

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