Hoogsteen Base Pairing (Molecular Biology)
Nucleic acid bases can form a variety of base pairs. In all canonical duplex
structures including B-DNA, A-DNA, and Z-DNA, the so-called Watson-Crick base
pairs are found. The Watson-Crick base-pairings of guanine with cytosine and
adenine with thymine are shown in Figure 1. The G to C and A to T
complementarities are provided by specific hydrogen bond donors and acceptors
between the bases. In a G:C base pair three hydrogen bonds are found between GO6 and C-N4, G-N1 and C-N3, and G-N2 and C-O2 positions, and in an A:T base
pair two hydrogen bonds are found between A-N6 and T-O4, and A-N1 and T-N3
positions. The two C1′ atoms within a G:C base pair and an A:T base pair are
equidistant (~10.5 A). Thus the G:C and A:T base pairs in the Watson-Crick
conformation are nearly iso-structural, from the point of the view of the sugarphosphate backbone.
Figure 1. Schematic illustration of the A:T and G:C Watson-Crick and
Hoogsteen base pairs. Hydrogen bonds are shown as dashed lines, and the
distance between two C1′ atoms (shown as open squares) is drawn with a thin
line. The numbering system of the purine and pyrimidine rings is shown.
In earlier crystallographic analyses of nucleic acid base pairs, it was found that
an A:T base pair can also adopt a different conformation. Instead of using the N1
position of adenine to base pair with N3 of thymine, the N7 position of adenine was
used. This type of A:T base pair was named Hoogsteen base pair (1). A striking
difference between those two types of base pairs is that the C1′-C1′ distance in the
Hoogsteen base pair of 8.65 A is significantly shorter than that of the Watson-Crick
base pair of 10.5 A. Therefore the Hoogsteen base pair is not compatible structurally
with the Watson-Crick base pair in B-DNA. The incorporation of a Hoogsteen base
pair in B-DNA destabilizes the duplex structure. A similar G:C Hoogsteen base pair
is not stable unless the C is protonated at the N3 position.
However, certain chemical modifications may enhance the stability of the Hoogsteen
base pair. It was shown that the modified nucleoside 3-isodeoxyadenosine (iA) forms
a stable base pair with thymine (T) using the Hoogsteen conformation, and the iA:T
base pair is fully compatible with the normal Watson-Crick base pair as evident from
the stable duplex of d(CG[iA]TCG) 2 shown by NMR analysis (2). Another
modification which stabilizes the Hoogsteen base pair involves the use of 8-aminoadenine in which the amino group at the C8 position can form an additional hydrogen
bond with the O2 of thymine (3). Those modified bases may find applications when
the Hoogsteen base pairing is needed in nucleic acid structures.