The stereoelectronic effects of replacement of the phosphodiester linker in nucleic acids by a thioformacetal linker have been investigated by computational techniques. Ab initio studies of the potential energy surfaces of thioformacetal, methyl propyl sulfide, and methyl 2-methoxy ethyl sulfide were initially conducted at the 6-31G* level of theory. These studies show that COGS and OCSC dihedral angles have strong gauche preferences (3.1 and 1.3 kcal/mol). In contrast, CCCS, CCSC, and OCCS dihedral angles are observed to have global minima which are trans conformations. The results of the ab initio studies were subsequently used to obtain potential energy force field parameters for use in molecular mechanics and molecular dynamics studies. The molecular mechanics studies were centered on the pseudorotational pathways for 3’-thio, 2’-deoxyribose and 5’-thio, 2’-deoxyribose nucleosides (dA and dT). The results of the molecular mechanics and quantum mechanics studies lead to the conclusion that when sulfur occupies the O5’ position, it is generally unfavorable due to both steric and electronic effects. However, the opposite orientation substitution, in which sulfur is incorporated at the O3’ position, is found to be detrimental in the case of a B form type nucleic acid conformation but generally well tolerated in the case of an A form type nucleic acid conformation. These results have been subsequently confirmed in part by experimental studies. A second experimental result, namely that the 3’S-thioformacetal linker could adopt a (+g, +g) conformation in oligomers, was investigated using thymine dimers and high temperature molecular dynamics simulations. Such a conformer is in fact found as a low energy conformation and is characterized by the backbone dihedral angles epsilon, zeta, alpha, beta, and gamma having a unique and previously unobserved +g, +g, +g, t, t pattern of torsional values.