Molecular Dynamics Simulations of PNA·DNA and PNA·RNA Duplexes in Aqueous Solution

Soliva, Robert; Sherer, Edward C.; Luque, F. Javier; Laughton, Charles A.; Orozco, Modesto

doi:10.1021/ja000259h

Cited by 65 publications

(77 citation statements)

References 59 publications

(150 reference statements)

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“…The DNA moiety then becomes adapted to the PNA P-helix conformation rather than vice versa. These conclusions are in agreement with molecular dynamics studies (32)(33) and with the ''constrained flexibility'' concept developed for PNAs and their analogues (16), whereas they reverse the early concept of PNAs as molecules endowed with high conformational adaptability (9).…”

Section: Discussionsupporting

confidence: 88%

Insights into peptide nucleic acid (PNA) structural features: The crystal structure of a d -lysine-based chiral PNA–DNA duplex

Menchise

Simone

Tedeschi

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

145

164

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Peptide nucleic acids (PNAs) are oligonucleotide analogues in which the sugar-phosphate backbone has been replaced by a pseudopeptide skeleton. They bind DNA and RNA with high specificity and selectivity, leading to PNA-RNA and PNA-DNA hybrids more stable than the corresponding nucleic acid complexes. The binding affinity and selectivity of PNAs for nucleic acids can be modified by the introduction of stereogenic centers (such as D-Lys-based units) into the PNA backbone. To investigate the structural features of chiral PNAs, the structure of a PNA decamer containing three D-Lys-based monomers (namely H-GpnTpnApnGpnAdlTdlCdlApnCpnTpn-NH2, in which pn represents a pseudopeptide link and dl represents a D-Lys analogue) hybridized with its complementary antiparallel DNA has been solved at a 1.66-Å resolution by means of a single-wavelength anomalous diffraction experiment on a brominated derivative. The D-Lys-based chiral PNA-DNA (LPD) heteroduplex adopts the so-called P-helix conformation. From the substantial similarity between the PNA conformation in LPD and the conformations observed in other PNA structures, it can be concluded that PNAs possess intrinsic conformational preferences for the P-helix, and that their flexibility is rather restricted. The conformational rigidity of PNAs is enhanced by the presence of the chiral centers, limiting the ability of PNA strands to adopt other conformations and, ultimately, increasing the selectivity in molecular recognition. P eptide nucleic acids (PNAs) are oligonucleotide mimics in which the sugar-phosphate backbone has been replaced by a pseudopeptide skeleton, composed of N-(2-aminoethyl)glycine units (1) (Fig. 1). Nucleobases are linked to this skeleton through a two-atom carboxymethyl spacer.PNAs bind DNA and RNA with high specificity and selectivity, forming Watson-Crick base pairs and leading to PNA-RNA and PNA-DNA hybrids that are more stable than the corresponding nucleic acid complexes (2). Because of their high thermal stability and resistance to proteases and nucleases, PNAs are ideal candidates as antisense or antigene therapeutic agents (3-6) and are currently used as powerful tools in molecular biology and in diagnostics (7).Three-dimensional structures have been determined for the major families of PNA complexes by different techniques. A PNA-RNA duplex (8) and a PNA-DNA duplex (9) were characterized by NMR in solution, whereas a (PNA) 2 -DNA triplex (10) and three PNA-PNA duplexes (11-13) were solved by x-ray crystallography. The structural analysis in solution of the PNA-DNA (9) and PNA-RNA duplexes (8) showed that PNA, when hybridized to RNA, adopts an A-like helix, whereas, when hybridized to a complementary DNA strand, it adopts a conformation that is different from both the A and the B forms. The crystal structure of the (PNA) 2 -DNA triplex (10) also showed helical parameters significantly different from those of canonical DNA or RNA helical forms, defining a type of helix, named the P-helix, characterized by a small twist angle, a large x-displacem...

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Section: Discussionsupporting

confidence: 88%

Insights into peptide nucleic acid (PNA) structural features: The crystal structure of a d -lysine-based chiral PNA–DNA duplex

Menchise

Simone

Tedeschi

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

145

164

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“…The third structure was a dodecamer of PNA, in the P-form, with the same base-pair sequence as the DNA dodecamer. The PNA strand's peptide backbone was terminated with N-terminus and C-terminus end-groups, as reported by Shields et al (1998) and Soliva et al (2000) in their MD studies of PNA:DNA and PNA:RNA molecules.…”

Section: Model Constructionmentioning

confidence: 99%

Stability of free and mineral-protected nucleic acids: Implications for the RNA world

Swadling¹,

Coveney²,

Greenwell³

2012

Geochimica et Cosmochimica Acta

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Using molecular dynamics simulations we study the structural stability of three different nucleic acids intercalated within a magnesium aluminium layered double hydroxide (LDH) mineral, at varying degrees of hydration, and free in aqueous solution. The nucleotides investigated are ribose nucleic acid (RNA), deoxyribose nucleic acid (DNA) and peptide nucleic acid (PNA), all in duplex form. Our simulations show that DNA has enhanced Watson-Crick hydrogen-bonding when intercalated within the LDH clay interlayers, compared with intercalated RNA and PNA, whilst the reverse trend is found for the nucleic acids in bulk water. The tendency for LDH to alter the stability of the three nucleic acids persists for higher temperature and pressure conditions. The uncharged protein backbone of PNA is found to have a detrimental effect on the overall stability of the duplex, as it experiences a greatly reduced electrostatic interaction with the charged LDH sheets compared to RNA and DNA. Assuming an RNA world, in which RNA preceded the DNA/protein world, at some point in time DNA must have taken over the role as the information storage molecule from RNA. These results suggest that a mineral based origin of life may have favoured DNA as the information-storage biomolecule over potentially competing RNA and PNA, providing a route to modern biology from the RNA world.

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“…4 -7 We were not the only groups to capitalize on these methodological and technological advances as the field has seemed to collectively jump forward. To date, a wide repertoire of successes have been seen in simulations of DNA single strands, 8 duplexes, 9,10 triplexes, [11][12][13] quadruplexes, 14,15 and usual DNA structures such as zipper DNA, 16 modified backbones [17][18][19] and damaged DNA 20 -22, and also of RNA duplexes and higher order structures. 23 These simulations have shown that current molecular dynamics simulation methodologies cannot only reproduce experiment, but give insight beyond experiment, and even suggest novel experiments to address scientific problems.…”

Section: Successes Of Molecular Dynamics Applied To Nucleic Acidsmentioning

confidence: 99%

Molecular dynamics simulation of nucleic acids: Successes, limitations, and promise

2000

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Molecular Dynamics Simulations of PNA·DNA and PNA·RNA Duplexes in Aqueous Solution

Cited by 65 publications

References 59 publications

Insights into peptide nucleic acid (PNA) structural features: The crystal structure of a d -lysine-based chiral PNA–DNA duplex

Insights into peptide nucleic acid (PNA) structural features: The crystal structure of a d -lysine-based chiral PNA–DNA duplex

Stability of free and mineral-protected nucleic acids: Implications for the RNA world

Molecular dynamics simulation of nucleic acids: Successes, limitations, and promise

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