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Molecular dynamics simulation of PNPLA3 I148M polymorphism reveals reduced substrate access to the catalytic cavity
Yong-Ning Xin1, Yuqi Zhao, Zhong-Hua Lin
1College of Medicine and Pharmaceutics, Ocean University of China, Qingdao 266003, Shandong Province, China.
Abstract:
A missense mutation I148M in PNPLA3 (patatin-like phospholipase domain-containing 3 protein) is significantly correlated with nonalcoholic fatty liver disease (NAFLD). To glean insights into mutation's effect on enzymatic activity, we performed molecular dynamics simulation and flexible docking studies. Our data show that the size of the substrate-access entry site is significantly reduced in mutants, which limits the access of palmitic acid to the catalytic dyad. Besides, the binding free energy calculations suggest low affinity for substrate to mutant enzyme. The substrate-bound system simulations reveal that the spatial arrangement of palmitic acid is distinct in wild-type from that in mutant. The substrate recognition specificity is lost due to the loop where the I148M mutation was located. Our results provide strong evidence for the mechanism by which I148M affects the enzyme activity and suggest that mediating the dynamics may offer a potential avenue for NAFLD.
Insights
The I148M mutation in patatin-like phospholipase domain-containing 3 protein (PNPLA3) impairs its enzymatic activity, contributing to nonalcoholic fatty liver disease (NAFLD). This study reveals how the mutation alters substrate access and recognition, offering potential therapeutic targets for NAFLD.
Area of Science:
- Biochemistry
- Molecular Biology
- Genetics
Background:
- A specific missense mutation, I148M, in the patatin-like phospholipase domain-containing 3 protein (PNPLA3) is strongly associated with nonalcoholic fatty liver disease (NAFLD).
- Understanding the molecular mechanisms by which this mutation affects PNPLA3 enzymatic function is crucial for developing targeted therapies for NAFLD.
Purpose of the Study:
- To investigate the impact of the I148M mutation on the enzymatic activity of PNPLA3.
- To elucidate the structural and dynamic changes induced by the I148M mutation that contribute to NAFLD pathogenesis.
Main Methods:
- Molecular dynamics (MD) simulations were employed to analyze the protein structure and dynamics.
- Flexible docking studies were performed to assess substrate binding affinity and specificity.
- Binding free energy calculations were utilized to quantify the interaction strength between the enzyme and its substrate.
Main Results:
- The I148M mutation significantly reduces the size of the substrate-access entry site, hindering palmitic acid access to the catalytic dyad.
- Binding free energy calculations indicate a lower affinity of the mutant enzyme for its substrate.
- Simulations of substrate-bound systems show altered spatial arrangement of palmitic acid and loss of substrate recognition specificity due to conformational changes in a key loop.
Conclusions:
- The I148M mutation in PNPLA3 impairs enzyme activity by altering substrate access and recognition mechanisms.
- These findings provide a mechanistic basis for the link between PNPLA3 I148M and NAFLD.
- Modulating protein dynamics presents a potential therapeutic strategy for managing NAFLD.
