title: Free energy component analysis: application to the "Z-phobicity" of A-T base pairs.
abstract: We have carried out molecular dynamics/free energy perturbation calculations on the double helical hexamer d(CGCGCG)2 in both B and Z forms. The third C.G base pair was "mutated" to T-A in both B and Z-DNA. It is known experimentally that replacement of a C.G with a T-A base pair in an alternating CG sequence raises the energy of the Z form relative to the B form by approximately 1 kcal mole-1. We have carried out free energy component calculations to assess the reason for the "Z-phobicity" of T-A base pairs. There are two major contributions. The primary contribution is from the intra-base pair interactions of the mutated base pair itself which disfavor T-A relative to C.G in the Z form by congruent to 1.4 kcal mole-1. A secondary contribution of 0.4 kcal mole-1 arises because the two cytosines on the strand where G is mutated to A disfavor T-A relative to C.G in the Z form by 1.9 kcal mole-1, while the guanines flanking the C on the complementary strand stabilize the T-A base pair relative to the C.G in the Z form by 1.5 kcal mole-1. The effect of the phosphates, non-neighboring nucleotides and intramolecular energies of the base pair being mutated are all small and come close to canceling each other, leading to a net calculated free energy for T-A Z-phobicity of 1.7 kcal mole-1.
authors.affiliation: Department of Pharmaceutical Chemistry, University of California, San Francisco 94143.
authors.forename: S B
authors.initials: SB
authors.lastname: Singh
authors.forename: D A
authors.initials: DA
authors.lastname: Pearlman
authors.forename: P A
authors.initials: PA
authors.lastname: Kollman
mesh_terms: D001482:Base Composition; D001483:Base Sequence; D004247:DNA / Q000737:chemistry*; D008969:Molecular Sequence Data; D009690:Nucleic Acid Conformation; D009994:Osmolar Concentration; D013816:Thermodynamics
chemical_list: D004247:DNA