How does the protein environment optimize the thermodynamics of thiol sulfenylation? Insights from model systems to QM/MM calculations on human 2-Cys peroxiredoxin

Oláh, Julianna; Bergen, Laura van; Proft, Frank De; Roos, Goedele

doi:10.1080/07391102.2014.907543

Cited by 9 publications

(13 citation statements)

References 40 publications

(41 reference statements)

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“…It has been proposed that Ser26 does not govern ligand selectivity through sidechain H bond interactions, since a fully transport-active AdiC S26A mutant shows a normal capacity to distinguish Arg + from Arg +2 11 , 30 . However experimental and theoretical studies, however, have shown that water molecules can, in some cases, take over the role of the mutated residue within the binding pocket 31 , 32 . One can therefore not totally rule out the possibility that the Ser26 sidechain or a replacing bound water molecule might act in a local mechanism.…”

Section: Discussionmentioning

confidence: 99%

Molecular mechanism of substrate selectivity of the arginine-agmatine Antiporter AdiC

Krammer

Gibbons

Roos

et al. 2018

Sci Rep

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The arginine-agmatine antiporter (AdiC) is a component of an acid resistance system developed by enteric bacteria to resist gastric acidity. In order to avoid neutral proton antiport, the monovalent form of arginine, about as abundant as its divalent form under acidic conditions, should be selectively bound by AdiC for transport into the cytosol. In this study, we shed light on the mechanism through which AdiC distinguishes Arg+ from Arg2+ of arginine by investigating the binding of both forms in addition to that of divalent agmatine, using a combination of molecular dynamics simulations with molecular and quantum mechanics calculations. We show that AdiC indeed preferentially binds Arg+. The weaker binding of divalent compounds results mostly from their greater tendency to remain hydrated than Arg+. Our data suggests that the binding of Arg+ promotes the deprotonation of Glu208, a gating residue, which in turn reinforces its interactions with AdiC, leading to longer residence times of Arg+ in the binding site. Although the total electric charge of the ligand appears to be the determinant factor in the discrimination process, two local interactions formed with Trp293, another gating residue of the binding site, also contribute to the selection mechanism: a cation-π interaction with the guanidinium group of Arg+ and an anion-π interaction involving Glu208.

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Section: Discussionmentioning

confidence: 99%

Molecular mechanism of substrate selectivity of the arginine-agmatine Antiporter AdiC

Krammer

Gibbons

Roos

et al. 2018

Sci Rep

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“…Due to the size of the protein (10079 atoms) structural optimization is performed using the CHARMM27 force field 28 for protein and water molecules, while the capping N-terminal N-carbamoyl-alanine (NCB) residue is described by a custom CHARMM topology file, for which atom typing and assignment of parameters and charges are taken from an analogous residue. Details of the topology file and of the parameters of NCB can be found in the supporting information of a previous publication by some of the present authors 29 . All modeling calculations are carried out using the CHARMM software package 30 .…”

Section: Methodsmentioning

confidence: 99%

“…All modeling calculations are carried out using the CHARMM software package 30 . The S -form of cysteine is created using a previously published patch residue 29 . Parameters for the S -form were previously published 31,32 .…”

Section: Methodsmentioning

confidence: 99%

Convergence of Atomic Charges with the Size of the Enzymatic Environment

Vanpoucke

Oláh

Proft

et al. 2015

J. Chem. Inf. Model.

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Atomic charges are a key concept to give more insight into the electronic structure and chemical reactivity. The Hirshfeld-I partitioning scheme applied to the model protein human 2-cysteine peroxiredoxin thioredoxin peroxidase B is used to investigate how large a protein fragment needs to be in order to achieve convergence of the atomic charge of both, neutral and negatively charged residues. Convergence in atomic charges is rapidly reached for neutral residues, but not for negatively charged ones. This study pinpoints difficulties on the road towards accurate modeling of negatively charged residues of large biomolecular systems in a multiscale approach.3

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“…All of the above mechanisms favor thiolate form over thiol; therefore, their efficiency is highly sensitive to cysteine pKa (the more nuanced discussion of the pKa dependence can be found elsewhere 41 , 42 ). More generally, in the context of structured proteins the efficiency of these reactions can be greatly influenced by electrostatic and steric factors and vary by many orders of magnitude 43 .…”

Section: Resultsmentioning

confidence: 99%

Simple MD-based model for oxidative folding of peptides and proteins

Izmailov

Podkorytov

Skrynnikov

2017

Sci Rep

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Significant strides have been recently made to fold peptides and small proteins in silico using MD simulations. However, facilities are currently lacking to include disulfide bonding in the MD models of protein folding. To address this problem, we have developed a simple empirical protocol to model formation of disulfides, which is perturbation-free, retains the same speed as conventional MD simulations and allows one to control the reaction rate. The new protocol has been tested on 15-aminoacid peptide guanylin containing four cysteine residues; the net simulation time using Amber ff14SB force field was 61 μs. The resulting isomer distribution is in qualitative agreement with experiment, suggesting that oxidative folding of guanylin in vitro occurs under kinetic control. The highly stable conformation of the so-called isomer 2(B) has been obtained for full-length guanylin, which is significantly different from the poorly ordered structure of the truncated peptide PDB ID 1GNB. In addition, we have simulated oxidative folding of guanylin within the 94-aminoacid prohormone proguanylin. The obtained structure is in good agreement with the NMR coordinates 1O8R. The proposed modeling strategy can help to explore certain fundamental aspects of protein folding and is potentially relevant for manufacturing of synthetic peptides and recombinant proteins.

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How does the protein environment optimize the thermodynamics of thiol sulfenylation? Insights from model systems to QM/MM calculations on human 2-Cys peroxiredoxin

Abstract: Protein thiol/sulfenic acid oxidation potentials provide a tool to select specific oxidation agents, but are experimentally difficult to obtain. Here, insights into the thiol sulfenylation thermodynamics is obtained from model calculations on small systems and from a quantum

Cited by 9 publications

References 40 publications

Molecular mechanism of substrate selectivity of the arginine-agmatine Antiporter AdiC

Molecular mechanism of substrate selectivity of the arginine-agmatine Antiporter AdiC

Convergence of Atomic Charges with the Size of the Enzymatic Environment

Simple MD-based model for oxidative folding of peptides and proteins

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