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ABSTRACT yDNA is a base-modified nucleic acid duplex containing size-expanded nucleobases. Base-modified nucleic acids could expand the genetic alphabet and thereby enhance the functional potential of DNA. Unrestrained 100 ns MD simulations were performed in explicit solvent on the yDNA NMR sequence [5′(yA T yA yA T yA T T yA T)2] and two modeled yDNA duplexes, [5′(yC yC G yC yC G G yC G G)2] and [(yT5′ G yT A yC yG C yA yG T3′)•(yA5′ C T C yG C G yT A yC A3′)]. The force field parameters for the yDNA bases were derived in consistent with the well-established AMBER force field. Our results show that DNA backbone can withstand the stretched size of the bases retaining the Watson-Crick base pairing in the duplexes. The duplexes retained their double helical structure throughout the simulations accommodating the strain due to expanded bases in the backbone torsion angles, sugar pucker and helical parameters. The effect of the benzo-expansion is clearly reflected in the extended C1′-C1′ distances and enlarged groove widths. The size expanded base modification leads to reduction in base pair twist resulting in larger overlapping area between the stacked bases, enhancing inter and intra strand stacking interactions in yDNA in comparison with BDNA. This geometry could favour enhanced interactions with the groove binders and DNA binding proteins., 2016. © 2015 Wiley Periodicals, Inc. Biopolymers 105: 55-64, 2016 [ABSTRACT FROM AUTHOR]