title: Molecular dynamics simulations and oxidation rates of methionine residues of granulocyte colony-stimulating factor at different pH values.
abstract: To understand the connection between the conformation of a protein molecule and the oxidation of its methionine residues, we measured the rates of oxidation of methionine residues by H(2)O(2) in granulocyte colony-stimulating factor (G-CSF) as a function of pH and also studied the structural properties of this protein as a function of pH via molecular dynamics simulations. We found that each of the four methionine groups in G-CSF have significant and different rates of oxidation as a function of pH. Moreover, Met(1), in the unstructured N-terminal region, has a rate of oxidation as low as half that of free methionine. The structural properties of G-CSF as a function of pH are evaluated in terms of properties such as hydrogen bonding, deviations from X-ray structure, helical/helical packing, and the atomic covariance fluctuation matrix of alpha-carbons. We found that dynamics (structural fluctuations) are essential in explaining oxidation and that a static picture, such as that resulting from X-ray data, fails in this regard. Moreover, the simulation results also indicate that the solvent-accessible area, traditionally used to measure solvent accessibility of a protein site, of the sulfur atom of methionine residues does not correlate well with the rate of oxidation. Instead, we identified a structural property, average two-shell water coordination number, that correlates well with measured oxidation rates.
authors.affiliation: Department of Chemical Engineering, Massachusetts Institute of Technology, 77 Massachusetts Avenue, 66-458, Cambridge, Massachusetts 02139-4301, USA.
authors.forename: Jhih-Wei
authors.initials: JW
authors.lastname: Chu
authors.forename: Jin
authors.initials: J
authors.lastname: Yin
authors.forename: Daniel I C
authors.initials: DI
authors.lastname: Wang
authors.forename: Bernhardt L
authors.initials: BL
authors.lastname: Trout
mesh_terms: D000595:Amino Acid Sequence; D003198:Computer Simulation; D018360:Crystallography, X-Ray; D016179:Granulocyte Colony-Stimulating Factor / Q000737:chemistry*; D006861:Hydrogen Peroxide / Q000737:chemistry; D006863:Hydrogen-Ion Concentration; D008715:Methionine / Q000737:chemistry*; D008956:Models, Chemical; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010084:Oxidation-Reduction; D011487:Protein Conformation; D017433:Protein Structure, Secondary; D012997:Solvents / Q000737:chemistry; D013816:Thermodynamics
chemical_list: D012997:Solvents; D016179:Granulocyte Colony-Stimulating Factor; D008715:Methionine; D006861:Hydrogen Peroxide