title: Molecular dynamics simulation of PNPLA3 I148M polymorphism reveals reduced substrate access to the catalytic cavity.
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.
authors.affiliation: College of Medicine and Pharmaceutics, Ocean University of China, Qingdao 266003, Shandong Province, China.
authors.forename: Yong-Ning
authors.initials: YN
authors.lastname: Xin
authors.forename: Yuqi
authors.initials: Y
authors.lastname: Zhao
authors.forename: Zhong-Hua
authors.initials: ZH
authors.lastname: Lin
authors.forename: Xiangjun
authors.initials: X
authors.lastname: Jiang
authors.forename: Shi-Ying
authors.initials: SY
authors.lastname: Xuan
authors.forename: Jingfei
authors.initials: J
authors.lastname: Huang
mesh_terms: D020134:Catalytic Domain; D019295:Computational Biology / Q000379:methods; D004789:Enzyme Activation; D004795:Enzyme Stability; D006801:Humans; D007532:Isoleucine / Q000737:chemistry / Q000235:genetics; D008049:Lipase / Q000737:chemistry* / Q000235:genetics; D008565:Membrane Proteins / Q000737:chemistry* / Q000235:genetics; D056004:Molecular Dynamics Simulation; D046912:Multiprotein Complexes / Q000737:chemistry; D020125:Mutation, Missense; D019308:Palmitic Acid / Q000737:chemistry; D011110:Polymorphism, Genetic; D011485:Protein Binding; D017433:Protein Structure, Secondary; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D000217:Acyltransferases; D054512:Phospholipases A2, Calcium-Independent
chemical_list: D007532:Isoleucine; D008049:Lipase; D008565:Membrane Proteins; D046912:Multiprotein Complexes; D019308:Palmitic Acid; C533682:PNPLA3 protein, human; D000217:Acyltransferases; D054512:Phospholipases A2, Calcium-Independent