Insights into structure, dynamics and hydration of locked nucleic acid (LNA) strand-based duplexes from molecular dynamics simulations

Abstract

Locked nucleic acid (LNA) is a chemically modified nucleic acid with its sugar ring locked in an RNA-like (C3′-endo) conformation. LNAs show extraordinary thermal stabilities when hybridized with DNA, RNA or LNA itself. We performed molecular dynamics simulations on five isosequential duplexes (LNA–DNA, LNA–LNA, LNA–RNA, RNA–DNA and RNA–RNA) in order to characterize their structure, dynamics and hydration. Structurally, the LNA–DNA and LNA–RNA duplexes are found to be similar to regular RNA–DNA and RNA–RNA duplexes, whereas the LNA–LNA duplex is found to have its helix partly unwound and does not resemble RNA–RNA duplex in a number of properties. Duplexes with an LNA strand have on average longer interstrand phosphate distances compared to RNA–DNA and RNA–RNA duplexes. Furthermore, intrastrand phosphate distances in LNA strands are found to be shorter than in DNA and slightly shorter than in RNA. In case of induced sugar puckering, LNA is found to tune the sugar puckers in partner DNA strand toward C3′-endo conformations more efficiently than RNA. The LNA–LNA duplex has lesser backbone flexibility compared to the RNA–RNA duplex. Finally, LNA is less hydrated compared to DNA or RNA but is found to have a well-organized water structure.

Molecular dynamics simulation of DNA duplex, analog of PPT (polypurine tract), its conformation and hydration: a theoretical study

“…This indicates that the first strand, which is purine rich, is slightly more hydrated because of the size of the bases and the corresponding functional groups. This is consistent with estimates from spectroscopic measurements of 11-12 water molecules per nucleotide (Saenger, 1984;Pande and Nilsson, 2008).…”

Inclusion of methoxy groups inverts the thermodynamic stabilities of DNA–RNA hybrid duplexes: A molecular dynamics simulation study

“…The resulting RNA-like conformation of oligonucleotides due to 2 -O-methyl modifications was confirmed by CD spectroscopy [24,29], NMR spectroscopy [30], and X-ray studies [31]. Modelling studies have also supported the A-like conformation to 2 -O-methyl modified nucleic acids in line with the experimental studies [32][33][34]. In addition to A-like conformation, the 2 -O-methyl modified duplexes have under-winding helical structure suggested by recent studies [34].…”

“…Leapfrog integrator was employed to integrate the Newton's equation of motion and the coordinates were saved for every 5 ps for further analysis. During the MD simulations, a weak harmonic constraint with a force constant 4.0 kcal mol −1 Å −2 was applied on the terminal hydrogen bonds in order to avoid the base pair opening [33,[40][41]. VMD [59] and Curves+ [60] programs were used for analysis.…”

“…It is known that the ribose and deoxyribose sugars exhibit conformation in C3 -endo and C2 -endo regions respectively that results in A-like and B-like conformations to RNA and DNA duplexes, respectively [33,[40][41][42]. Since DNA-RNA hybrid has both DNA and RNA strands in the same duplex, the global conformation of the duplex is A/B-like or close to A-like depending on the sequence [28,41].…”

Targeting the serrated pathway of colorectal cancer with mutation in BRAF

“…Bearing this in mind, therapeutic correction of alternative RAC1b splicing will probably have to follow a similar tiling approach in order to find the most effective ASO to induce skipping exon 3b and thus decrease RAC1b protein and tumor cell survival. Meanwhile, alternative chemical modifications of the nucleotide furanose ring have generated new types of ASOs such as phosphoroamidate morpholino oligomers (PMO), [176], peptide nucleic acids (PNA) [177], and locked nucleic acids (LNA) [178] with improved target affinity, biostability and pharmacokinetics [179]. Alternatively, tumor-cell targeted nanoparticles were described as carriers for the systemic administration of siRNAs in animal models [180] and human clinical trials [181] and produced a gene-specific inhibition via the expected an RNA interference mechanism [182].…”