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Title: RNA-Binding Affinities and Crystal Structure of Oligonucleotides Containing Five-Atom Amide-Based Backbone Structures

Abstract

Among the hundreds of nucleic acid analogues that have been studied over the last two decades only very few exhibit backbones with linkers between residues that are either shorter or longer than the four-atom linker O3{prime}-P-O5{prime}-C5{prime} connecting sugar ring moieties in DNA and RNA. 2{prime}-Deoxyribonucleoside dimers connected by a five-atom linker O3{prime}-CH*(CH{sub 3})-CO-NH-CH{sub 2} (* designates a chiral center) were reported to lead to only a slight destabilization of RNA-DNA hybrids in which the DNA strand contained one or several of these amide-linked dimers (De Napoli, L., Iadonisi, A., Montesarchio, D., Varra, M., and Piccialli, G. (1995) Synthesis of thymidine dimers containing a new internucleosidic amide linkage and their incorporation into oligodeoxyribonucleotides, Bioorg. Med. Chem. Lett. 5, 1647-1652). To analyze the influence of various chemistries of such five-atom amide linkers on the RNA-binding affinity of modified DNA strands, we have synthesized five different amide-linked dimers, including structures with homochiral linkers of the type X3{prime}-C*H(CH{sub 3})-CO-NH-CH{sub 2} (X = O, CH{sub 2}) as well as the corresponding analogues carrying methoxy groups at the 2{prime}-position of the 3{prime}-nucleosides. We have conducted a detailed thermodynamic analysis of duplex formation between the modified DNA and RNA, with the DNA strands containing between one andmore » seven consecutive modified dimers. Some of the five-atom-linked dimers lead to significantly higher RNA-binding affinities compared with that of native DNA. Interestingly, the linkers with opposite stereochemistry at the chiral center stabilize duplexes between the modified DNA and RNA to different degrees. CD spectroscopy in solution and a crystal structure of an RNA-DNA duplex with a single amide-linked dimer demonstrate that the longer amide backbones do not disrupt the duplex geometry. These observations provide further evidence that stable cross-pairing between two different types of nucleic acids does not require the numbers of atoms linking their individual residues to match.« less

Authors:
; ; ; ;  [1]
  1. SFIT
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org.:
USDOE
OSTI Identifier:
1007742
Resource Type:
Journal Article
Journal Name:
Biochemistry-US
Additional Journal Information:
Journal Volume: 45; Journal Issue: (26) ; 07, 2006; Journal ID: ISSN 0006-2960
Country of Publication:
United States
Language:
ENGLISH
Subject:
36 MATERIALS SCIENCE; AFFINITY; AMIDES; ATOMS; CRYSTAL STRUCTURE; DIMERS; DNA; GEOMETRY; NUCLEIC ACIDS; OLIGONUCLEOTIDES; RESIDUES; RNA; SACCHAROSE; SPECTROSCOPY; STEREOCHEMISTRY; SYNTHESIS; THERMODYNAMICS; THYMIDINE

Citation Formats

Pallan, Pradeep S, von Matt, Peter, Wilds, Christopher J, Altmann, Karl-Heinz, Egli, Martin, Novartis), and Vanderbilt). RNA-Binding Affinities and Crystal Structure of Oligonucleotides Containing Five-Atom Amide-Based Backbone Structures. United States: N. p., 2010. Web. doi:10.1021/bi060354o.
Pallan, Pradeep S, von Matt, Peter, Wilds, Christopher J, Altmann, Karl-Heinz, Egli, Martin, Novartis), & Vanderbilt). RNA-Binding Affinities and Crystal Structure of Oligonucleotides Containing Five-Atom Amide-Based Backbone Structures. United States. doi:10.1021/bi060354o.
Pallan, Pradeep S, von Matt, Peter, Wilds, Christopher J, Altmann, Karl-Heinz, Egli, Martin, Novartis), and Vanderbilt). Mon . "RNA-Binding Affinities and Crystal Structure of Oligonucleotides Containing Five-Atom Amide-Based Backbone Structures". United States. doi:10.1021/bi060354o.
@article{osti_1007742,
title = {RNA-Binding Affinities and Crystal Structure of Oligonucleotides Containing Five-Atom Amide-Based Backbone Structures},
author = {Pallan, Pradeep S and von Matt, Peter and Wilds, Christopher J and Altmann, Karl-Heinz and Egli, Martin and Novartis) and Vanderbilt)},
abstractNote = {Among the hundreds of nucleic acid analogues that have been studied over the last two decades only very few exhibit backbones with linkers between residues that are either shorter or longer than the four-atom linker O3{prime}-P-O5{prime}-C5{prime} connecting sugar ring moieties in DNA and RNA. 2{prime}-Deoxyribonucleoside dimers connected by a five-atom linker O3{prime}-CH*(CH{sub 3})-CO-NH-CH{sub 2} (* designates a chiral center) were reported to lead to only a slight destabilization of RNA-DNA hybrids in which the DNA strand contained one or several of these amide-linked dimers (De Napoli, L., Iadonisi, A., Montesarchio, D., Varra, M., and Piccialli, G. (1995) Synthesis of thymidine dimers containing a new internucleosidic amide linkage and their incorporation into oligodeoxyribonucleotides, Bioorg. Med. Chem. Lett. 5, 1647-1652). To analyze the influence of various chemistries of such five-atom amide linkers on the RNA-binding affinity of modified DNA strands, we have synthesized five different amide-linked dimers, including structures with homochiral linkers of the type X3{prime}-C*H(CH{sub 3})-CO-NH-CH{sub 2} (X = O, CH{sub 2}) as well as the corresponding analogues carrying methoxy groups at the 2{prime}-position of the 3{prime}-nucleosides. We have conducted a detailed thermodynamic analysis of duplex formation between the modified DNA and RNA, with the DNA strands containing between one and seven consecutive modified dimers. Some of the five-atom-linked dimers lead to significantly higher RNA-binding affinities compared with that of native DNA. Interestingly, the linkers with opposite stereochemistry at the chiral center stabilize duplexes between the modified DNA and RNA to different degrees. CD spectroscopy in solution and a crystal structure of an RNA-DNA duplex with a single amide-linked dimer demonstrate that the longer amide backbones do not disrupt the duplex geometry. These observations provide further evidence that stable cross-pairing between two different types of nucleic acids does not require the numbers of atoms linking their individual residues to match.},
doi = {10.1021/bi060354o},
journal = {Biochemistry-US},
issn = {0006-2960},
number = (26) ; 07, 2006,
volume = 45,
place = {United States},
year = {2010},
month = {3}
}