A Computational Study of Expanded Heterocyclic Nucleosides in DNA

Abstract

The first molecular dynamics study of a series of heterospacer-expanded tricyclic bases in DNA using modified force field parameters in AMBER is detailed. The expanded purine nucleoside monomers have been designed to probe the effects of a heteroaromatic spacer ring on the structure, function, and dynamics of the DNA helix. The heterobase scaffold has been expanded with a furan, pyrrole, or thiophene spacer ring. This structural modification increases the polarizability of the bases and provides an additional hydrogen bond donor with the amine hydrogen of the pyrrole ring or hydrogen bond acceptor with the furan or thiophene ring free electron pairs. The polarizability of the expanded bases were determined by AM1 calculations and the results of the MD simulations of 20-mers predict that the modified curvature of the expanded base leads to a much larger major groove, while the effect on the minor groove is negligible. Overall, the structure resembles A-DNA. MD simulations of 10-mers suggest that the balance between base pairing vs. base stacking and intercalation can be shifted towards the latter due to the increased surface area and polarizability of the expanded bases.

Flexible Nucleobase Analogues: Novel Tools for Exploring Nucleic Acids

“…These analogues were initially developed as dimensional probes for investigating enzyme binding sites, but also exhibited fluorescent properties (Leonard and Hiremath 1986;Spencer et al 1974;Secrist et al 1972a, b;Barrio et al 1972). The SeleyRadtke and Tor groups have continued this work with their hetero-expanded purines (4) and extended pyrimidines (5 and 6) (Wauchope et al 2010(Wauchope et al , 2012aO'Daniel et al 2008;Temburnikar et al 2013Temburnikar et al , 2014Tor et al 2007). The use of heterocyclic spacers serves to increase polarizability and aromatic character as well as to provide a less drastic curvature to the expanded base, thereby decreasing the base pair distance in DNA.…”

Probing the Effects of Pyrimidine Functional Group Switches on Acyclic Fleximer Analogues for Antiviral Activity

“…By altering different components of the nucleoside, such as the nucleobase, sugar moiety, and phosphate group, medicinal chemists can develop novel analogues for their use in various therapeutics [1,2]. Over the past decade, research in the Seley-Radtke lab has focused on the development of various types of flexible nucleoside analogues, called “fleximers”, that have demonstrated the ability to overcome point mutations within the binding site of biologically significant enzymes (Figure 1) [3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20].…”

Mechanistic studies in the synthesis of a series of thieno-expanded xanthosine and guanosine nucleosides

“…In addition, molecular dynamics calculations have shown that inclusion of the heteroaromatic spacer will increase the overall aromaticity and polarizability for the base, which in turn, will result in an increase in stacking effects, an important factor in stabilization of the DNA helix 34–37…”