title: Molecular dynamic simulation to explore the molecular basis of Btk-PH domain interaction with Ins(1,3,4,5)P4.
abstract: Bruton's tyrosine kinase contains a pleckstrin homology domain, and it specifically binds inositol 1,3,4,5-tetrakisphosphate (Ins(1,3,4,5)P4), which is involved in the maturation of B cells. In this paper, we studied 12 systems including the wild type and 11 mutants, K12R, S14F, K19E, R28C/H, E41K, L11P, F25S, Y40N, and K12R-R28C/H, to investigate any change in the ligand binding site of each mutant. Molecular dynamics simulations combined with the method of molecular mechanics/Poisson-Boltzmann solvent-accessible surface area have been applied to the twelve systems, and reasonable mutant structures and their binding free energies have been obtained as criteria in the final classification. As a result, five structures, K12R, K19E, R28C/H, and E41K mutants, were classified as "functional mutations," whereas L11P, S14F, F25S, and Y40N were grouped into "folding mutations." This rigorous study of the binding affinity of each of the mutants and their classification provides some new insights into the biological function of the Btk-PH domain and related mutation-causing diseases.
authors.affiliation: Center for Systems Biology, Soochow University, Suzhou 215006, China.
authors.forename: Dan
authors.initials: D
authors.lastname: Lu
authors.forename: Junfeng
authors.initials: J
authors.lastname: Jiang
authors.forename: Zhongjie
authors.initials: Z
authors.lastname: Liang
authors.forename: Maomin
authors.initials: M
authors.lastname: Sun
authors.forename: Cheng
authors.initials: C
authors.lastname: Luo
authors.forename: Bairong
authors.initials: B
authors.lastname: Shen
authors.forename: Guang
authors.initials: G
authors.lastname: Hu
mesh_terms: D000077329:Agammaglobulinaemia Tyrosine Kinase; D019943:Amino Acid Substitution; D001665:Binding Sites / Q000235:genetics; D003198:Computer Simulation; D006801:Humans; D006860:Hydrogen Bonding; D007295:Inositol Phosphates / Q000378:metabolism*; D008024:Ligands; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D016297:Mutagenesis, Site-Directed; D050505:Mutant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D017510:Protein Folding; D054730:Protein Interaction Domains and Motifs; D011505:Protein-Tyrosine Kinases / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*
chemical_list: D007295:Inositol Phosphates; D008024:Ligands; D050505:Mutant Proteins; C081655:inositol-1,3,4,5-tetrakisphosphate; D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase; C000625949:BTK protein, human