Theoretical Chemistry Accounts

, 131:1293 | Cite as

Semimicroscopic investigation of active site pK a values in peptidylarginine deiminase 4

Regular Article

Abstract

Peptidylarginine deiminase 4 (PAD4), also known as protein arginine deiminase 4, performs a post-translational deimination that converts arginine to citrulline. The dysregulation of PAD4 has been implicated in a number of diseases, including rheumatoid arthritis (RA) and cancer. This makes PAD4 an important therapeutic target. To develop small-molecule inhibitors as potential treatments, it is advantageous if the catalytic mechanism is well understood. The protonation states of the active site residues, which have long been under controversy, have a direct impact on the catalytic mechanism. Two competing mechanisms are under investigation in the current literature. The first is a reverse protonation mechanism that depends on the active site histidine and cysteine existing as an ion pair. The second is a substrate-assisted mechanism that depends on the active site histidine and cysteine being neutral. This study uses the semimicroscopic protein dipoles Langevin dipoles (PDLD/S) linear response approximation method in the MOLARIS software package to calculate the change in solvation energy of moving the residue from water to the protein interior, and then using that information to assess the protonation states of the active site residues of PAD4. Results from these calculations suggest that in the enzyme–substrate complex of PAD4, the cysteine and histidine are protonated and deprotonated, respectively, and are therefore both neutral, analogous to the proposed protonation states of the active site residues in the Michaelis complex in the substrate-assisted mechanism.

Keywords

Protein arginine deiminase 4 Peptidylarginine deiminase 4 PAD4 PADIV Rheumatoid arthritis Substrate-assisted mechanism 

Notes

Acknowledgments

This work was supported by the University of Colorado Colorado Springs. Dr. Arieh Warshel and Dr. Zhen Tao Chu at the University of Southern California are thanked for access to the MOLARIS software and for helpful discussions. Dr. James Vivian is also thanked for helpful discussions.

Supplementary material

214_2012_1293_MOESM1_ESM.pdf (31 kb)
Supplementary material 1 (PDF 30 kb)

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Copyright information

© Springer-Verlag Berlin Heidelberg 2012

Authors and Affiliations

  1. 1.Department of Chemistry and BiochemistryUniversity of Colorado Colorado SpringsColorado SpringsUSA

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