6#1

Tautomerism as a Constraint on the Composition of Alternative Nucleotide Alphabets

D. A. Mac Dónaill
Department of Chemistry, Trinity College, Dublin 2, Republic of Ireland. E-mail: dmcdonll@tcd.ie

Abstract:

    The factors determining the composition of the nucleotide alphabet are not self-evident. While, straightforward extensions to the alphabet such as iC:iG have received some theoretical attention, more exotic nucleotide pairs, such as $\alpha$:$\Gamma$, $\beta$:$\delta$, and $\kappa$:X, have been ignored. At the current state of knowledge the possibility of viable alternative nucleotide alphabets remains an intriguing possibility. In this paper the broader space of potential letters is considered in terms of hydrogen donor-acceptor patterns. Quantum chemical simulations at the PM3 semi-empirical level of approximation are employed to examine the stability of different tautomeric forms of candidate letters. The results suggest that tautomeric instability favoring hydroxyl elements over keto groups is one of the critical constraints on viable alternative alphabets. Rotation of a hydroxyl group changes the expressed hydrogen donor/acceptor pattern, destroying the integrity of the principal recognition feature. Two distinct alphabets appear viable, one containing the familiar aA:T/U and C:G, and a second containing just $\kappa$:X. Thus tautomerism offers an explanation for the composition of the natural alphabet, while posing challenges for the engineering of alternative alphabets.