Solvent effects on model d(CG·G)₇ and d(TA·T)₇ DNA triple helices

Using free energy molecular mechanics, we find that the molecular effects of solvent are critical in determining relative stabilities in DNA triple helices or triplexes. The continuum solvent model is unable to differentiate the thermodynamics reflecting the basic solvation differences around the occupied major groove in triplexes. In order to avoid the local minimum problem, which is a major limitation of any modeling study, we started our computations with multiple structures rather than relying on the optimization of a single reference structure. By constructing triplex models with different initial helical twists, helical rises, and sugar‐pucker permutations, we explore the potential surface and the structural preference with respect to these variations. We find that in order to accommodate a third strand in triplex formation, the backbone geometry of the B‐DNA duplex target has to be adjusted into A‐DNA‐like form with a deep major groove. This is achieved by concerted adjustment in torsions β, ε, and ζ around the phosphate groups. However, the sugar pucker displays a more rich variation, resulting in conformations not usually associated with the canonical duplex structures. © 1995 John Wiley & Sons, Inc.