PyCPR – a python-based implementation of the Conjugate Peak Refinement (CPR) algorithm for finding transition state structures

Gisdon, Florian J; Culka, Martin; Ullmann, G. Matthias

doi:10.1007/s00894-016-3116-8

Cited by 10 publications

(9 citation statements)

References 39 publications

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“…The RMS gradient threshold for all minimizations and surface scans was set to 0.02 kcal/(mol Å). The stable minimized intermediates and transition state estimates from surface scans were further refined using the PyCPR implementation of the conjugated peak refinement (CPR) method in order to obtain estimates of the transition states. In addition, PyCPR was also used to derive a path between two stable intermediates de novo, or a roughly optimized path obtained from the growing string method was used as an input.…”

Section: Methodsmentioning

confidence: 99%

Breaking Benzene Aromaticity—Computational Insights into the Mechanism of the Tungsten-Containing Benzoyl-CoA Reductase

et al. 2017

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Aromatic compounds are environmental pollutants with toxic and carcinogenic properties. Despite the stability of aromatic rings, bacteria are able to degrade the aromatic compounds into simple metabolites and use them as growth substrates under oxic or even under anoxic conditions. In anaerobic microorganisms, most monocyclic aromatic growth substrates are converted to the central intermediate benzoyl-coenzyme A, which is enzymatically reduced to cyclohexa-1,5-dienoyl-CoA. The strictly anaerobic bacterium Geobacter metallireducens uses the class II benzoyl-CoA reductase complex for this reaction. The catalytic BamB subunit of this complex harbors an active site tungsten-bis-pyranopterin cofactor with the metal being coordinated by five protein/cofactor-derived sulfur atoms and a sixth, so far unknown, ligand. Although BamB has been biochemically and structurally characterized, its mechanism still remains elusive. Here we use continuum electrostatic and QM/MM calculations to model benzoyl-CoA reduction by BamB. We aim to elucidate the identity of the sixth ligand of the active-site tungsten ion together with the interplay of the electron and proton transfer events during the aromatic ring reduction. On the basis of our calculations, we propose that benzoyl-CoA reduction is initiated by a hydrogen atom transfer from a W(IV) species with an aqua ligand, yielding W(V)-[OH] and a substrate radical intermediate. In the next step, a proton-assisted second electron transfer takes place with a conserved active-site histidine serving as the second proton donor. Interestingly, our calculations suggest that the electron for the second reduction step is taken from the pyranopterin cofactors rather than from the tungsten ion. The resulting cationic radical, which is distributed over both pyranopterins, is stabilized by conserved anionic amino acid residues. The stepwise mechanism of the reduction shows similarities to the Birch reduction known from organic chemistry. However, the strict coupling of protons and electrons allows the reaction to proceed under milder conditions.

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Section: Methodsmentioning

confidence: 99%

Breaking Benzene Aromaticity—Computational Insights into the Mechanism of the Tungsten-Containing Benzoyl-CoA Reductase

et al. 2017

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“…A first estimate for the reaction coordinate was obtained by potential energy surface scan (PES), followed by minimization. Promising pathways were then optimized by modified nudged elastic band (NEB) 40 and conjugate peak refinement (CPR) 41 with our own python implementation PyCPR 42 , using the BP86 functional as the QM method. Energetically feasible reaction paths were further refined using CPR and the B3LYP functional, which was also used for vibration frequency calculations.…”

Section: Methodsmentioning

confidence: 99%

Mechanisms and Specificity of Phenazine Biosynthesis Protein PhzF

Diederich

Leypold

Culka

et al. 2017

Sci Rep

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Phenazines are bacterial virulence and survival factors with important roles in infectious disease. PhzF catalyzes a key reaction in their biosynthesis by isomerizing (2 S,3 S)-2,3-dihydro-3-hydroxy anthranilate (DHHA) in two steps, a [1,5]-hydrogen shift followed by tautomerization to an aminoketone. While the [1,5]-hydrogen shift requires the conserved glutamate E45, suggesting acid/base catalysis, it also shows hallmarks of a sigmatropic rearrangement, namely the suprafacial migration of a non-acidic proton. To discriminate these mechanistic alternatives, we employed enzyme kinetic measurements and computational methods. Quantum mechanics/molecular mechanics (QM/MM) calculations revealed that the activation barrier of a proton shuttle mechanism involving E45 is significantly lower than that of a sigmatropic [1,5]-hydrogen shift. QM/MM also predicted a large kinetic isotope effect, which was indeed observed with deuterated substrate. For the tautomerization, QM/MM calculations suggested involvement of E45 and an active site water molecule, explaining the observed stereochemistry. Because these findings imply that PhzF can act only on a limited substrate spectrum, we also investigated the turnover of DHHA derivatives, of which only O-methyl and O-ethyl DHHA were converted. Together, these data reveal how PhzF orchestrates a water-free with a water-dependent step. Its unique mechanism, specificity and essential role in phenazine biosynthesis may offer opportunities for inhibitor development.

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“…Its trajectory was simulated using quantum-mechanical (QM)/MM calculations by starting from the reduced anionic FMNH – state. Using PyCPR 34 , we found a transition state at 16 kcal mol −1 in which the proton of FMNH − is at half distance between N1 of FMN and C6 of NCoA, and the HOMO is delocalized over both ring systems (Fig. 9).…”

Section: Resultsmentioning

confidence: 99%

“…The RMS gradient threshold of 0.04 kcal (mol Å) −1 was used for all minimizations and surface scans. For finding reliable transition states, we started from these estimates of the intermediates and transition state and applied the PyCPR 34 implementation of the conjugated peak refinement method 60 .…”

Section: Methodsmentioning

confidence: 99%

Low potential enzymatic hydride transfer via highly cooperative and inversely functionalized flavin cofactors

et al. 2019

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Hydride transfers play a crucial role in a multitude of biological redox reactions and are mediated by flavin, deazaflavin or nicotinamide adenine dinucleotide cofactors at standard redox potentials ranging from 0 to –340 mV. 2-Naphthoyl-CoA reductase, a key enzyme of oxygen-independent bacterial naphthalene degradation, uses a low-potential one-electron donor for the two-electron dearomatization of its substrate below the redox limit of known biological hydride transfer processes at E °’ = −493 mV. Here we demonstrate by X-ray structural analyses, QM/MM computational studies, and multiple spectroscopy/activity based titrations that highly cooperative electron transfer ( n = 3) from a low-potential one-electron (FAD) to a two-electron (FMN) transferring flavin cofactor is the key to overcome the resonance stabilized aromatic system by hydride transfer in a highly hydrophobic pocket. The results evidence how the protein environment inversely functionalizes two flavins to switch from low-potential one-electron to hydride transfer at the thermodynamic limit of flavin redox chemistry.

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PyCPR – a python-based implementation of the Conjugate Peak Refinement (CPR) algorithm for finding transition state structures

Cited by 10 publications

References 39 publications

Breaking Benzene Aromaticity—Computational Insights into the Mechanism of the Tungsten-Containing Benzoyl-CoA Reductase

Breaking Benzene Aromaticity—Computational Insights into the Mechanism of the Tungsten-Containing Benzoyl-CoA Reductase

Mechanisms and Specificity of Phenazine Biosynthesis Protein PhzF

Low potential enzymatic hydride transfer via highly cooperative and inversely functionalized flavin cofactors

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