No benefit from base stacking is observed for rates of electron transfer in DNA. This conclusion was drawn from experiments with a new DNA assay in which a radical cationic site, generated by strand cleavage, can be reduced by the guanine bases in the same DNA (the electron transfer is indicated by arrows in the diagram). The distance dependence of this electron transfer step is determined by the chemical yield of the reduction product.

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Conformational free-energy differences are key quantities for understanding important phenomena in molecular biology that involve large structural changes of macromolecules. In this paper, an improved version of the confinement approach, which is based on earlier developments, determines the free energy of the individual states by progressively restraining the molecular conformations to pure harmonic basins, whose absolute free energy can be computed by normal-mode analysis. The method is used to calculate the free-energy difference between two structurally known molecular states of the alanine dipeptide in vacuo, and the β-hairpin from protein G with an implicit solvation model. In all cases, the confinement results are in excellent agreement with the ones obtained from equilibrium molecular dynamics simulations, which have a much larger computational cost. The systematic and statistical errors of the results are determined and the origin of the errors is identified. The sensitivity of the calculated free-energy differences to structure-based definitions of molecular states is discussed. A variant of the method, which closes the thermodynamic cycle by a quasi-harmonic rather than harmonic analysis, is proposed. The latter is proposed for possible use with explicit solvent simulations.