Molecular Mechanism of Protein Arginine Deiminase 2: A Study Involving Multiple Microsecond Long Molecular Dynamics Simulations

Erdem Cicek, Gerald Monard*, Fethiye Aylin Sungur*

*Bu çalışma için yazışmadan sorumlu yazar

Araştırma sonucu: ???type-name???Makalebilirkişi

Özet

Peptidylarginine deiminase 2 (PAD2) is a Ca2+-dependent enzyme that catalyzes the conversion of protein arginine residues to citrulline. This kind of structural modification in histone molecules may affect gene regulation, leading to effects that may trigger several diseases, including breast cancer, which makes PAD2 an attractive target for anticancer drug development. To design new effective inhibitors to control activation of PAD2, improving our understanding of the molecular mechanisms of PAD2 using up-to-date computational techniques is essential. We have designed five different PAD2-substrate complex systems based on varying protonation states of the active site residues. To search the conformational space broadly, multiple independent molecular dynamics simulations of the complexes have been performed. In total, 50 replica simulations have been performed, each of 1 μs, yielding a total simulation time of 50 μs. Our findings identify that the protonation states of Cys647, Asp473, and His471 are critical for the binding and localization of the N-α-benzoyl-l-arginine ethyl ester substrate within the active site. A novel mechanism for enzyme activation is proposed according to near attack conformers. This represents an important step in understanding the mechanism of citrullination and developing PAD2-inhibiting drugs for the treatment of breast cancer.

Orijinal dilİngilizce
Sayfa (başlangıç-bitiş)1286-1297
Sayfa sayısı12
DergiBiochemistry
Hacim61
Basın numarası13
DOI'lar
Yayın durumuYayınlandı - 5 Tem 2022

Bibliyografik not

Publisher Copyright:
© 2022 American Chemical Society. All rights reserved.

Parmak izi

Molecular Mechanism of Protein Arginine Deiminase 2: A Study Involving Multiple Microsecond Long Molecular Dynamics Simulations' araştırma başlıklarına git. Birlikte benzersiz bir parmak izi oluştururlar.

Alıntı Yap