title: Effect of the R119G mutation on human P5CR structure and its interactions with NAD: Insights derived from molecular dynamics simulation and free energy analysis.
abstract: Pyrroline-5-carboxylate reductase (P5CR), an enzyme with conserved housekeeping roles, is involved in the etiology of cutis laxa. While previous work has shown that the R119G point mutation in the P5CR protein is involved, the structural mechanism behind the pathology remains to be elucidated. In order to probe the role of the R119G mutation in cutis laxa, we performed molecular dynamics (MD) simulations, essential dynamics (ED) analysis, and Molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) binding free energy calculations on wild type (WT) and mutant P5CR-NAD complex. These MD simulations and ED analyses suggest that the R119G mutation decreases the flexibility of P5CR, specifically in the substrate binding pocket, which could decrease the kinetics of the cofactor entrance and egress. Furthermore, the MM-PBSA calculations suggest the R119G mutant has a lower cofactor binding affinity for NAD than WT. Our study provides insight into the possible role of the R119G mutation during interactions between P5CR and NAD, thus bettering our understanding of how the mutation promotes cutis laxa.
authors.affiliation: Laboratory of Molecular Cardiology, Department of Cardiology,The First Affiliated Hospital of Kunming Medical University, Kunming, PR China.
authors.forename: Peng
authors.initials: P
authors.lastname: Sang
authors.affiliation: Department of Computer Science, The Faculty of Basic Medicine, Kunming Medical University, Kunming, PR China.
authors.forename: Yue-Hui
authors.initials: YH
authors.lastname: Xie
authors.affiliation: Laboratory of Molecular Cardiology, Department of Cardiology,The First Affiliated Hospital of Kunming Medical University, Kunming, PR China.
authors.forename: Lin-Hua
authors.initials: LH
authors.lastname: Li
authors.affiliation: Laboratory of Molecular Cardiology, Department of Cardiology,The First Affiliated Hospital of Kunming Medical University, Kunming, PR China.
authors.forename: Yu-Jia
authors.initials: YJ
authors.lastname: Ye
authors.affiliation: Laboratory of Molecular Cardiology, Department of Cardiology,The First Affiliated Hospital of Kunming Medical University, Kunming, PR China.
authors.forename: Wei
authors.initials: W
authors.lastname: Hu
authors.affiliation: Laboratory of Molecular Cardiology, Department of Cardiology,The First Affiliated Hospital of Kunming Medical University, Kunming, PR China.
authors.forename: Jing
authors.initials: J
authors.lastname: Wang
authors.affiliation: Laboratory of Molecular Cardiology, Department of Cardiology,The First Affiliated Hospital of Kunming Medical University, Kunming, PR China.
authors.forename: Wen
authors.initials: W
authors.lastname: Wan
authors.affiliation: Laboratory of Molecular Cardiology, Department of Cardiology,The First Affiliated Hospital of Kunming Medical University, Kunming, PR China.
authors.forename: Rui
authors.initials: R
authors.lastname: Li
authors.affiliation: Laboratory of Molecular Cardiology, Department of Cardiology,The First Affiliated Hospital of Kunming Medical University, Kunming, PR China.
authors.forename: Long-Jun
authors.initials: LJ
authors.lastname: Li
authors.affiliation: Laboratory of Molecular Cardiology, Department of Cardiology,The First Affiliated Hospital of Kunming Medical University, Kunming, PR China.
authors.forename: Lin-Ling
authors.initials: LL
authors.lastname: Ma
authors.affiliation: Laboratory of Molecular Cardiology, Department of Cardiology,The First Affiliated Hospital of Kunming Medical University, Kunming, PR China.
authors.forename: Zhi
authors.initials: Z
authors.lastname: Li
authors.affiliation: Laboratory of Molecular Cardiology, Department of Cardiology,The First Affiliated Hospital of Kunming Medical University, Kunming, PR China; State Key Laboratory for Conservation and Utilization of Bio-Resources in Yunnan, Yunnan University, Kunming, PR China. Electronic address: shuqunliu@ynu.edu.cn.
authors.forename: Shu-Qun
authors.initials: SQ
authors.lastname: Liu
authors.affiliation: Laboratory of Molecular Cardiology, Department of Cardiology,The First Affiliated Hospital of Kunming Medical University, Kunming, PR China. Electronic address: zhhmeng@aliyun.com.
authors.forename: Zhao-Hui
authors.initials: ZH
authors.lastname: Meng
mesh_terms: D001120:Arginine / Q000235:genetics; D002384:Catalysis; D003483:Cutis Laxa / Q000209:etiology*; D004735:Energy Transfer; D005998:Glycine / Q000235:genetics; D006801:Humans; D007700:Kinetics; D056004:Molecular Dynamics Simulation; D009243:NAD / Q000737:chemistry / Q000378:metabolism*; D017354:Point Mutation; D011485:Protein Binding; D011762:Pyrroline Carboxylate Reductases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D000097502:delta-1-Pyrroline-5-Carboxylate Reductase
chemical_list: D001120:Arginine; D005998:Glycine; D009243:NAD; D011762:Pyrroline Carboxylate Reductases; D000097502:delta-1-Pyrroline-5-Carboxylate Reductase
keywords: Binding free energy; Cutis laxa; Molecular dynamics; P5CR