title: Free energy calculations for the relative binding affinity between DNA and lambda-repressor.
abstract: The change in the binding free energy between DNA and lambda-repressor resulting from a base substitution, thymine (T)-->deoxyuracil (abbreviated as U), was evaluated by the free energy perturbation method on the basis of molecular dynamics simulations for the DNA-lambda-repressor complex in water with all degrees of freedom and including long-range Coulomb interactions. The binding free energy change that we calculated (1.47 +/- 0.40 kcal/mol) was in good agreement with an experimental value (1.8 kcal/mol). We clarified why the small difference between T and U (CH(3) in T is replaced with H in U) caused such a significant change in the binding free energy: The substitution of CH(3) in T with H in U lowered the dissociated-state free energy level due to the gain of the hydration free energy. Furthermore, the T-->U substitution raised the free energy level in the associated state due to the loss of the favored van der Waals (vdW) interactions with the lambda-repressor amino acid residues. In other words, the amino acid residues of lambda-repressor can recognize the CH(3) in T through the vdW interactions with the CH(3). This recognition is enhanced in a water environment, because the hydrophobic CH(3) prefers the amino acid residues of lambda-repressor to water molecules.
authors.affiliation: Faculty of Science and Technology, Hirosaki University, 3 Bunkyo-cho, Hirosaki, Aomori 036-8561, Japan. msaito@si.hirosaki-u.ac.jp
authors.forename: Minoru
authors.initials: M
authors.lastname: Saito
authors.forename: Akinori
authors.initials: A
authors.lastname: Sarai
mesh_terms: D001665:Binding Sites; D003198:Computer Simulation; D004247:DNA / Q000737:chemistry* / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000737:chemistry* / Q000378:metabolism*; D008432:Mathematical Computing; D011485:Protein Binding; D012097:Repressor Proteins / Q000737:chemistry* / Q000378:metabolism*; D013941:Thymine / Q000737:chemistry; D014498:Uracil / Q000737:chemistry; D014764:Viral Proteins; D054334:Viral Regulatory and Accessory Proteins; D014867:Water / Q000737:chemistry
chemical_list: D004268:DNA-Binding Proteins; D012097:Repressor Proteins; D014764:Viral Proteins; D054334:Viral Regulatory and Accessory Proteins; C016649:phage repressor proteins; D014867:Water; D014498:Uracil; D004247:DNA; D013941:Thymine