title: Interaction and solvation energies of nonpolar DNA base analogues and their role in polymerase insertion fidelity.
abstract: Although DNA polymerase fidelity has been mainly ascribed to Watson-Crick hydrogen bonds, two nonpolar isosteres for thymine (T) and adenine (A)--difluorotoluene (F) and benzimidazole (Z) --effectively mimic their natural counterparts in polymerization experiments with pol I (KF exo-) [JC Morales and ET Kool. Nature Struct Biol, 5, 950-954, 1998]. By ab initio quantum chemical gas phase methods (HF/6-31G* and MP2/6-31G**) and a solvent phase method (CPCM-HF/6-31G**), we find that the A-F interaction energy is 1/3 the A-T interaction energy in the gas phase and unstable in the solvent phase. The F-Z and T-Z interactions are very weak and T-Z is quite unstable in the solvent. Electrostatic solvation energy calculations on F, Z and toluene yield that Z is two times, and F and toluene are five times, less hydrophilic than the natural bases. Of the new "base-pairs" (F-Z, T-Z, and F-A), only F-A formed an A-T-like arrangement in unconstrained optimizations. F-Z and T-Z do not freely form planar arrangements, and constrained optimizations show that large amounts of energy are required to make these pairs fit the exact A-T geometry, suggesting that the polymerase does not require all bases to conform to the exact A-T geometry. We discuss a model for polymerase/nucleotide binding energies and investigate the forces and conformational range involved in the polymerase geometrical selection.
authors.affiliation: Biology and Biotechnology Research Program, Lawrence Livermore National Lab, Livermore, CA 94550, USA. barsky@llnl.gov
authors.forename: D
authors.initials: D
authors.lastname: Barsky
authors.forename: E T
authors.initials: ET
authors.lastname: Kool
authors.forename: M E
authors.initials: ME
authors.lastname: Colvin
mesh_terms: D000225:Adenine / Q000737:chemistry; D020029:Base Pairing; D001562:Benzimidazoles / Q000737:chemistry; D004247:DNA / Q000737:chemistry* / Q000378:metabolism; D004256:DNA Polymerase I / Q000378:metabolism*; D004735:Energy Transfer; D008956:Models, Chemical; D012997:Solvents; D013941:Thymine / Q000737:chemistry; D014050:Toluene / Q000031:analogs & derivatives / Q000737:chemistry
chemical_list: D001562:Benzimidazoles; D012997:Solvents; D014050:Toluene; C110527:difluorotoluene; D004247:DNA; C031000:benzimidazole; D004256:DNA Polymerase I; D000225:Adenine; D013941:Thymine