title: Features of S-nitrosylation based on statistical analysis and molecular dynamics simulation: cysteine acidity, surrounding basicity, steric hindrance and local flexibility.
abstract: S-Nitrosylation is involved in protein functional regulation and cellular signal transduction. Although intensive efforts have been made, the molecular mechanisms of S-nitrosylation have not yet been fully understood. In this work, we carried out a survey on 213 protein structures with S-nitrosylated cysteine sites and molecular dynamic simulations of hemoglobin as a case study. It was observed that the S-nitrosylated cysteines showed a lower pKa, a higher population of basic residues, a lower population of big-volume residues in the neighborhood, and relatively higher flexibility. The case study of hemoglobin showed that, compared to that in the T-state, Cysβ93 in the R-state hemoglobin possessed the above structural features, in agreement with the previous report that the R-state was more reactive in S-nitrosylation. Moreover, basic residues moved closer to the Cysβ93 in the dep-R-state hemoglobin, while big-volume residues approached the Cysβ93 in the dep-T-state. Using the four characteristics, i.e. cysteine acidity, surrounding basicity, steric hindrance, and local flexibility, a 3-dimensional model of S-nitrosylation was constructed to explain 61.9% of the S-nitrosylated and 58.1% of the non-S-nitrosylated cysteines. Our study suggests that cysteine deprotonation is a prerequisite for protein S-nitrosylation, and these characteristics might be useful in identifying specificity of protein S-nitrosylation.
authors.affiliation: State Key Laboratory of Microbial Metabolism, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai 200240, China. yileizhao@sjtu.edu.cn.
authors.forename: Shangli
authors.initials: S
authors.lastname: Cheng
authors.forename: Ting
authors.initials: T
authors.lastname: Shi
authors.forename: Xiao-Lei
authors.initials: XL
authors.lastname: Wang
authors.forename: Juan
authors.initials: J
authors.lastname: Liang
authors.forename: Hongyi
authors.initials: H
authors.lastname: Wu
authors.forename: Lu
authors.initials: L
authors.lastname: Xie
authors.forename: Yixue
authors.initials: Y
authors.lastname: Li
authors.forename: Yi-Lei
authors.initials: YL
authors.lastname: Zhao
mesh_terms: D003545:Cysteine / Q000737:chemistry / Q000378:metabolism; D006454:Hemoglobins / Q000737:chemistry / Q000378:metabolism; D007700:Kinetics; D056004:Molecular Dynamics Simulation; D011499:Protein Processing, Post-Translational; D055550:Protein Stability; D011506:Proteins / Q000737:chemistry* / Q000378:metabolism*
chemical_list: D006454:Hemoglobins; D011506:Proteins; D003545:Cysteine