Global Structural Deformations Observed through Optimization Calculations of Smoothly Bent and Mini-Kinked Closed DNA

Abstract

Computational modeling of DNA has aided in understanding how the double helical structure can deform with and without the assistance of proteins. Such deformations allow for genetic and protein regulation as well as higher-order organization within the cell. A contributing factor to such deformability lies in the primary nucleotide sequence of DNA as some nucleotides have different intrinsic characteristics and helical configurations based on the local sequence context. For example, a pyrimidine-purine (YR) dinucleotide step has a greater degree of deformation when compared to pyrimidine-pyrimidine (YY) or purine-purine (RR) steps. We explore this sequence dependence through minimum-energy optimization calculations with various DNA conformational rest state and initial conditions that include smoothly-bent and mini-kinked closed structures. Optimization calculations were initially conducted on various 150-nucleotide sequences consisting of adenine and guanine with multiple initial states and a minimum of two force fields, one based on ideal B-DNA conditions and another with sequence dependency. From these initial optimization results, variant sequences were generated by replacing specific purine nucleotides by pyrimidines to examine pyrimidine-purine and purine-pyrimidine dinucleotide steps on global deformation. One of the initial sequence optimization calculations resulted in closed structures that contained multiple kinked regions. Although bending such as this is seen in DNA containing poly-A tracts, this sequence contains multiple shortened adenine patches that outnumber the number of kinked regions. For this sequence, variants were generated with a variety of asymmetric purine to pyrimidine replacements to observe any possible deviations from the original optimized structure. These studies provide a step forward in understanding the effect of sequence on naturally-occurring circular DNA structures of various lengths.