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Molecular Mechanism of Protein Arginine Deiminase 2: A Study Involving Multiple Microsecond Long Molecular Dynamics
Erdem Cicek1, Gerald Monard2, Fethiye Aylin Sungur1
1Informatics Institute, Computational Science and Engineering, Istanbul Technical University, TR-34469 Istanbul, Turkey.
Biochemistry
|June 23, 2022
Summary
Peptidylarginine deiminase 2 (PAD2) enzyme activity is crucial for gene regulation and linked to breast cancer. Understanding PAD2
Area of Science:
- Biochemistry
- Enzymology
- Molecular Biology
Background:
- Peptidylarginine deiminase 2 (PAD2) is a calcium-dependent enzyme.
- PAD2 catalyzes arginine to citrulline conversion, impacting gene regulation.
- PAD2 dysregulation is implicated in diseases like breast cancer, making it an anticancer drug target.
Purpose of the Study:
- To elucidate the molecular mechanisms of PAD2.
- To identify key factors influencing PAD2 activity and substrate binding.
- To provide a foundation for developing novel PAD2-inhibiting anticancer drugs.
Main Methods:
- Designed five PAD2-substrate complex systems with varied active site protonation states.
- Performed 50 independent 1 μs molecular dynamics simulations (50 μs total).
- Utilized computational techniques to analyze conformational space and binding dynamics.
Main Results:
- Identified critical protonation states of Cys647, Asp473, and His471 for substrate binding.
- Determined the importance of these residues for substrate localization in the active site.
- Proposed a novel enzyme activation mechanism based on near-attack conformers.
Conclusions:
- The protonation states of specific active site residues are essential for PAD2 function.
- A new mechanism for PAD2 activation has been elucidated.
- Findings advance the understanding of citrullination and support PAD2-targeted breast cancer therapy development.
