Yong-Ning Xin, Yuqi Zhao, and Zhong-Hua Lin contributed equally to this work.
Molecular dynamics simulation of PNPLA3 I148M polymorphism reveals reduced substrate access to the catalytic cavity†
Article first published online: 5 NOV 2012
Copyright © 2012 Wiley Periodicals, Inc.
Proteins: Structure, Function, and Bioinformatics
Volume 81, Issue 3, pages 406–414, March 2013
How to Cite
Xin, Y.-N., Zhao, Y., Lin, Z.-H., Jiang, X., Xuan, S.-Y. and Huang, J. (2013), Molecular dynamics simulation of PNPLA3 I148M polymorphism reveals reduced substrate access to the catalytic cavity. Proteins, 81: 406–414. doi: 10.1002/prot.24199
Author Contributions: Yong-Ning Xin, Yuqi Zhao and Zhong-Hua Lin conceived, designed, and performed the experiments. Xiangjun Jiang analyzed the results and revised the manuscript. Shi-Ying Xuan and Jingfei Huang supervised the work and wrote the manuscript with support from all authors.
- Issue published online: 28 JAN 2013
- Article first published online: 5 NOV 2012
- Accepted manuscript online: 8 OCT 2012 04:00AM EST
- Manuscript Revised: 20 SEP 2012
- Manuscript Accepted: 20 SEP 2012
- Manuscript Received: 22 MAY 2012
- National Natural Science Foundation of China. Grant Numbers: 31123005, 81170337
- Chinese Academy of Sciences. Grant Number: Y002731071
- Shandong Provincial Natural Science Foundation, China. Grant Number: ZR2009CM015
- National Basic Research Program of China. Grant Number: 2009CB941300
- nonalcoholic fatty liver disease;
- missense mutation;
- molecular dynamics simulations
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. Proteins 2013. © 2012 Wiley Periodicals, Inc.