Complexes formed by 6-mer of single-stranded homo-nucleotides and poly(3,4-ethylenedioxythiophene), a π-conjugated polymer, have been investigated from both experimental and theoretical points of view. UV-Vis absorption and circular dichroism spectra indicate that adenine and cytosine homo-nucleotides form stable and compact adducts with the conducting polymer, which are stabilized by non-specific electrostatic interactions. In contrast, complexes involving the guanine homonucleotide are clearly dominated by specific hydrogen bonds. A hierarchical modeling approach has been used to gain some information of the complex formed by the homo-nucleotide of guanine and the polymer at both the molecular and electronic levels. Atomistic molecular dynamics simulations reveal that upon complexation, the B-DNA conformation of the homo-nucleotide unfolds into a completely disordered arrangement, which allows the simultaneous formation of N–HO and N–HS hydrogen bonds, N–Hπ, π–π stacking and electrostatic interactions with the extended polymer molecule. In spite of such variety of interactions, specific hydrogen bonds have been found to be the most abundant and decisive in this complex. This study has been complemented by ab initio and density functional theory calculations to examine the specific interactions between 1-methylguanine and 3,4-ethylene-dioxythiophene (G:EDOT). The energy decomposition analyses performed show that the stability of the different structures is governed by the attractive electrostatic interaction and reveal the reason why the N–HO hydrogen bond is the strongest specific interaction between these two molecules.