Nucleic Acids Research Advance Access originally published online on September 28, 2007
Nucleic Acids Research 2007 35(19):6611-6624; doi:10.1093/nar/gkm612
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Nucleic Acids Research, 2007, Vol. 35, No. 19 6611-6624
© 2007 The Author(s)
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Structural Biology |
Backbone-base inclination as a fundamental determinant of nucleic acid self- and cross-pairing
1Department of Biochemistry, School of Medicine, Vanderbilt University, Nashville, TN 37232, USA, 2Alta Scuola Pedagogica, CH-6600 Locarno and 3Actelion Pharmaceuticals Ltd., CH-4123 Allschwil, Switzerland
*To whom correspondence should be addressed. Tel: +1 615 343 8070; Fax: +1 615 322 7122; Email: martin.egli{at}vanderbilt.edu
Received July 5, 2007. Revised July 25, 2007. Accepted July 26, 2007.
The crystal structure of the duplex formed by oligo(2',3'-dideoxy-ß-D-glucopyranosyl)nucleotides (homo-DNA) revealed strongly inclined backbone and base-pair axes [Egli,M., Pallan,P.S., Pattanayek,R., Wilds,C.J., Lubini,P., Minasov,G., Dobler,M., Leumann,C.J. and Eschenmoser,A. (2006) Crystal structure of homo-DNA and nature's choice of pentose over hexose in the genetic system. J. Am. Chem. Soc., 128, 10847–10856]. This inclination is easily perceived because homo-DNA exhibits only a modest helical twist. Conversely, the tight coiling of strands conceals that the backbone-base inclinations for A- (DNA and RNA) and B-form (DNA) duplexes differ considerably. We have defined a parameter 
B that corresponds to the local inclination between sugar-phosphate backbone and base plane in nucleic acid strands. Here, we show its biological significance as a predictive measure for the relative strand polarities (antiparallel, aps, or parallel, ps) in duplexes of DNA, RNA and artificial nucleic acid pairing systems. The potential of formation of ps duplexes between complementary 16-mers with eight A and U(T) residues each was investigated with DNA, RNA, 2'-O-methylated RNA, homo-DNA and p-RNA, the ribopyranosyl isomer of RNA. The thermodynamic stabilities of the corresponding aps duplexes were also measured. As shown previously, DNA is capable of forming both ps and aps duplexes. However, all other tested systems are unable to form stable ps duplexes with reverse Watson–Crick (rWC) base pairs. This observation illustrates the handicap encountered by nucleic acid systems with inclinations B that differ significantly from 0° to form a ps rWC paired duplex. Accordingly, RNA with a backbone-base inclination of –30°, pairs strictly in an aps fashion. On the other hand, the more or less perpendicular orientation of backbone and bases in DNA allows it to adopt a ps rWC paired duplex. In addition to providing a rationalization of relative strand polarity with nucleic acids, the backbone-base inclination parameter is also a determinant of cross-pairing. Thus, systems with strongly deviating B angles will not pair with each other. Nucleic acid pairing systems with significant backbone-base inclinations can also be expected to display different stabilities depending on which terminus carries unpaired nucleotides. The negative inclination of RNA is consistent with the higher stability of duplexes with 3'- compared to those with 5'-dangling ends.