The stepwise dissociation of the Zn(II)-bound Atox1 homodimer and its energetic asymmetry

Fortino, Mariagrazia; Schifino, Gioacchino; Vitone, Daniele; Arnesano, Fabio; Pietropaolo, Adriana

doi:10.1016/j.ica.2023.121452

Cited by 1 publication

(5 citation statements)

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“…This free energy value is comparable to that of the Atox1-dissociated state (6.3 kcal/mol). Furthermore, it aligns with the free energetics of the Atox1-Zn(II)-Atox1 homodimer, where the dissociation of the first Atox1 monomer requires 6 kcal/mol, while the complete detachment of the zinc ion from the complex, achieved through the dissociation of the second Atox1 monomer, is predicted to necessitate 11 kcal/mol …”

Section: Resultssupporting

confidence: 63%

“…Furthermore, it aligns with the free energetics of the Atox1-Zn(II)-Atox1 homodimer, where the dissociation of the first Atox1 monomer requires 6 kcal/mol, while the complete detachment of the zinc ion from the complex, achieved through the dissociation of the second Atox1 monomer, is predicted to necessitate 11 kcal/ mol. 43 The evolutions of the Cu(I)-Cys12 distance during the Atox1 dissociation process and those of the Cu(I)-Cys18 and Cu(I)-Cys15 distances during the Mnk1 dissociation process are illustrated in Figures S2−S4, respectively. These distances…”

Section: ■ Results and Discussionmentioning

confidence: 99%

“…29−34 Various contributions, aimed at predicting the structural and functional properties of the metallochaperone Atox1, P-type ATPases, 23,24,32,35,36 and other biological systems, 37−40 have been recently reported, within the framework of well-tempered and parallel bias metadynamics (PBMetaD). 41−43 A simulation workflow, based on the combination of freeenergy perturbation (FEP) theory 44 and PBMetaD, 45,46 was recently reported 43 and has been proven to adequately predict the dissociation of the zinc ion from the Atox1 homodimer. 43 In this study, we employed the same FEP/PBMetaD simulation workflow to predict the Cu(I) exchange mechanism.…”

Section: ■ Introductionmentioning

confidence: 99%

“…41−43 A simulation workflow, based on the combination of freeenergy perturbation (FEP) theory 44 and PBMetaD, 45,46 was recently reported 43 and has been proven to adequately predict the dissociation of the zinc ion from the Atox1 homodimer. 43 In this study, we employed the same FEP/PBMetaD simulation workflow to predict the Cu(I) exchange mechanism. The simulations started from the NMR structure of Cu(I) coordinated to both Atox1 and the first MBD of the Menkes protein (Mnk1).…”

Section: ■ Introductionmentioning

confidence: 99%

“…Over the years, several computational studies − have been conducted to clarify the structural details and the associated properties of bioinorganic systems. These analyses provide quantitative insights into the microscopic events defining the coordination of inorganic species within biomolecules. − Various contributions, aimed at predicting the structural and functional properties of the metallochaperone Atox1, P-type ATPases, ,,,, and other biological systems, − have been recently reported, within the framework of well-tempered and parallel bias metadynamics (PBMetaD). − …”

Section: Introductionmentioning

confidence: 99%

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Unraveling Copper Exchange in the Atox1-Cu(I)-Mnk1 Heterodimer: A Simulation Approach

Fortino,

Arnesano,

Pietropaolo

2024

J. Phys. Chem. B

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Copper, an essential metal for various cellular processes, requires tight regulation to prevent cytotoxicity. Intracellular pathways crucial for maintaining optimal copper levels involve soluble and membrane transporters, namely, metallochaperones and P-type ATPases, respectively. In this study, we used a simulation workflow based on free-energy perturbation (FEP) theory and parallel bias metadynamics (PBMetaD) to predict the Cu(I) exchange mechanism between the human Cu(I) chaperone, Atox1, and one of its two physiological partners, ATP7A. ATP7A, also known as the Menkes disease protein, is a transmembrane protein and one of the main copper-transporting ATPases. It pumps copper into the trans-Golgi network for the maturation of cuproenzymes and is also essential for the efflux of excess copper across the plasma membrane. In this analysis, we utilized the nuclear magnetic resonance (NMR) structure of the Cu(I)-mediated complex between Atox1 and the first soluble domain of the Menkes protein (Mnk1) as a starting point. Independent free-energy simulations were conducted to investigate the dissociation of both Atox1 and Mnk1. The calculations revealed that the two dissociations require free energy values of 6.3 and 6.2 kcal/mol, respectively, following a stepwise dissociation mechanism.

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Section: Resultssupporting

confidence: 63%

Section: ■ Results and Discussionmentioning

confidence: 99%