TY - JOUR
T1 - Molecular Mechanism of Protein Arginine Deiminase 2
T2 - A Study Involving Multiple Microsecond Long Molecular Dynamics Simulations
AU - Cicek, Erdem
AU - Monard, Gerald
AU - Sungur, Fethiye Aylin
N1 - Publisher Copyright:
© 2022 American Chemical Society. All rights reserved.
PY - 2022/7/5
Y1 - 2022/7/5
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85134083514&partnerID=8YFLogxK
U2 - 10.1021/acs.biochem.2c00158
DO - 10.1021/acs.biochem.2c00158
M3 - Article
C2 - 35737372
AN - SCOPUS:85134083514
SN - 0006-2960
VL - 61
SP - 1286
EP - 1297
JO - Biochemistry
JF - Biochemistry
IS - 13
ER -