Dynamics of terminal fraying-peeling and hydrogen bonds dictates the sequential vs. cooperative melting pathways of nanoscale DNA and PNA triplexes

Mandal, S and Ganesh, KN and Maiti, PK (2024) Dynamics of terminal fraying-peeling and hydrogen bonds dictates the sequential vs. cooperative melting pathways of nanoscale DNA and PNA triplexes. In: Nanoscale .

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Abstract

Peptide nucleic acids (PNAs) are charge-neutral synthetic DNA/RNA analogues. In many aspects of biology and biotechnology, the details of DNA and PNA melting reaction coordinates are crucial, and their associative/dissociative details remain inadequately understood. In the current study, we have attempted to gain insights into comparative melting pathways and binding affinity of iso-sequences of an 18-mer PNA-DNA-PNA triplex and the analogous DNA-DNA-DNA triplex, and DNA-DNA and PNA-DNA duplexes. It is intriguing that while the DNA-DNA-DNA triplex melts in two sequential steps, the PNA-DNA-PNA triplex melts in a single step and the mechanistic aspects for this difference are still not clear. We report an all-atom molecular dynamics simulation of both complexes in the temperature range of 300 to 500 K with 20 K intervals. Based on the trajectory analysis, we provide evidence that the association and dissociation are dictated by the differences in fraying-peeling effects from either terminus to the center in a zipper pattern among the PNA-DNA-PNA triplex and DNA-DNA-DNA triplexes. These are shown to be governed by the different characteristics of H-bonding, RMSD, and Free Energy Landscape (FEL) as analyzed by PCA, leading to the DNA-DNA-DNA triplex exhibiting sequential melting, while the PNA-DNA-PNA triplex shows cooperative melting of the whole fragment in a single-step. The PNA-DNA-PNA triplex base pairs are thermodynamically more stable than the DNA-DNA-DNA triplex, with the binding affinity of PNA-TFO to the PNA : DNA duplex being higher than that of DNA-TFO to the DNA : DNA duplex. The investigation of the association/dissociation of PNA-TFO to the PNA-DNA duplex has relevance and importance in the emerging effective applications of oligonucleotide therapy. © 2024 The Royal Society of Chemistry.

Item Type:	Journal Article
Publication:	Nanoscale
Publisher:	Royal Society of Chemistry
Additional Information:	The copyright for this article belongs to Royal Society of Chemistry.
Keywords:	Binding energy; Bioinformatics; DNA sequences; Free energy; Hydrogen bonds; Melting; Molecular dynamics; Oligonucleotides; Reaction kinetics, 'current; Binding affinities; DNA duplexes; DNA triplexes; Gain insight; Nano scale; Peptide nucleic acid; Reaction coordinates; Single-step; Synthetic DNA, DNA
Department/Centre:	Division of Physical & Mathematical Sciences > Physics
Date Deposited:	31 Jul 2024 05:17
Last Modified:	31 Jul 2024 05:17
URI:	http://eprints.iisc.ac.in/id/eprint/85732

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