The calculated free energy effects of 5‐methyl cytosine on the B to Z transition in DNA

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Abstract
We have examined the free energy effects of 5-methylation of cytosine on the B ⟷ Z conformational equilibrium in DNA. Free energy differences were calculated using the free energy perturbation approach, which uses an easily derived equation from classical statistical mechanics to relate the free energy difference between two states to the ensemble average of the potential energy difference between the states. Calculations were carried both in explicit solvent and (for comparison) in vacuo. The free energy values obtained for the explicit solvent systems are total free energies, with contributions from all parts of the system (solvent + solute), and so are relevant to the B ⟷ Z transitions observed under real(physiological) conditions. We calculate that in solution, methylation makes the B → Z transition more favorable by about −0.4 kcal/mole base pair (bp) in free energy. This value compares well with approximate experimentally derived values of about −0.3 kcal/ mole-bp. We also discuss a method for determining the free energy difference between conformational states poorly maintained by a potential energy model. Finally, the effects of methylation on the melting temperature of DNA are examined.