title: Contribution of Electrostatics to the Kinetics of Electron Transfer from NADH-Cytochrome b5 Reductase to Fe(III)-Cytochrome b5.
abstract: Brownian dynamics (BD) simulations provide here a theoretical atomic-level treatment of the reduction of human ferric cytochrome b5 (cyt b5) by NADH-cytochrome b5 reductaste (cyt b5r) and several of its mutants. BD is used to calculate the second-order rate constant of electron transfer (ET) between the proteins for direct correlation with experiments. Interestingly, the inclusion of electrostatic forces dramatically increases the reaction rate of the native proteins despite the overall negative charge of both proteins. The role played by electrostatic charge distribution in stabilizing the ET complexes and the role of mutations of several amino acid residues in stabilizing or destabilizing the complexes are analyzed. The complex with the shortest ET reaction distance (d = 6.58 Å) from rigid body BD is further subjected to 1 ns of molecular dynamics (MD) in a periodic box of TIP3P water to produce a more stable complex allowed by flexibility and with a shorter average reaction distance d = 6.02 Å. We predict a docking model in which the following ion-ion interactions are dominant (cyt b5r/cyt b5): Lys162-Heme O1D/Lys163-Asp64/Arg91-Heme O1A/Lys125-Asp70.
authors.affiliation: Department of Chemistry, Tennessee Technological University , Cookeville, Tennessee 38505, United States.
authors.forename: Sireesha
authors.initials: S
authors.lastname: Kollipara
authors.affiliation: Department of Chemistry, Tennessee Technological University , Cookeville, Tennessee 38505, United States.
authors.forename: Shivakishore
authors.initials: S
authors.lastname: Tatireddy
authors.affiliation: Department of Chemistry, Tennessee Technological University , Cookeville, Tennessee 38505, United States.
authors.forename: Thusitha
authors.initials: T
authors.lastname: Pathirathne
authors.affiliation: Department of Chemistry, Tennessee Technological University , Cookeville, Tennessee 38505, United States.
authors.forename: Lasantha K
authors.initials: LK
authors.lastname: Rathnayake
authors.affiliation: Department of Chemistry, Tennessee Technological University , Cookeville, Tennessee 38505, United States.
authors.forename: Scott H
authors.initials: SH
authors.lastname: Northrup
mesh_terms: D019943:Amino Acid Substitution; D001665:Binding Sites; D042966:Cytochrome-B(5) Reductase / Q000737:chemistry* / Q000378:metabolism; D015786:Cytochromes b5 / Q000737:chemistry* / Q000378:metabolism; D004579:Electron Transport; D004583:Electrons; D005182:Flavin-Adenine Dinucleotide / Q000737:chemistry* / Q000378:metabolism; D006418:Heme / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D007700:Kinetics; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D009154:Mutation; D009243:NAD / Q000737:chemistry* / Q000378:metabolism; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D017433:Protein Structure, Secondary; D055672:Static Electricity; D013816:Thermodynamics
chemical_list: D009243:NAD; D005182:Flavin-Adenine Dinucleotide; D006418:Heme; D015786:Cytochromes b5; D042966:Cytochrome-B(5) Reductase