Multiscale modeling of nucleic acids: Insights into DNA flexibility

Abstract

The elastic rod theory is used together with all-atom normal mode analysis in implicit solvent to characterize the mechanical flexibility of duplex DNA. The bending, twisting, stretching rigidities extracted from all-atom simulations (on linear duplexes from 60 to 150 base pairs in length and from 94 base-pair minicircles) are in reasonable agreement with experimental results. We focus on salt concentration and sequence effects on the overall flexibility. Bending persistence lengths are about 20% higher than most experimental estimates, but the transition from low-salt to high-salt behavior is reproduced well, as is the dependence of the stretching modulus on salt (which is opposite to that of bending). CTG and CGG trinucleotide repeats, responsible for several degenerative disorders, are found to be more flexible than random DNA, in agreement with several recent studies, whereas poly (dA).poly(dT) is the stiffest sequence we have encountered. The results suggest that current all-atom potentials, which were parameterized on small molecules and short oligonucleotides, also provide a useful description of duplex DNA at much longer length scales.

DNA Elasticity from Short DNA to Nucleosomal DNA

“…Bomble and Case studied the elastic properties of linear (60 − 150 bps) and circular ds-DNA (94 bps) using elastic rod theory along with normal mode analysis in implicit solvent and calculated the effects of salt concentration as well as DNA sequence on its flexibility. 44 They observed a reasonable agreement with the experimental results.…”

On the Relationship between DNA Periodicity and Local Chromatin Structure

“…Numerous papers (most recently [29], for example) describing a relationship between the periodicity of the (not-T)(A/T)G (also referred to as VWG) motif and chromatin structure have cited the work by Baldi et al as a starting point. Perhaps the relationship between C(A/T)G and chromatin structure is instead due to the extreme flexibility of this trinucleotide [14]. It should also be noted that CTG, one of the six codons that code for leucine, is the most commonly used codon in human, while CAG, one of just two codons that code for glutamine, is the third most common -together they account for over 7% of all codons.…”

“…These ∼10 bp periodicities are strongly correlated with nucleosome positioning, supporting the hypothesis that periodic sequence elements in phase with the DNA helix are related to large-scale bending of the DNA molecule. DNA bendability has been extensively modeled [10], [11], [12], and experimentally measured [13], with a general consensus that poly(dA:dT) tracts are extremely stiff [14], while some short sequences are very flexible, particularly the CA/TG dinucleotide and the CAG/CTG trinucleotide [15], and others such as TA are context-dependent [10].…”

Coupled binding–bending–folding: The complex conformational dynamics of protein-DNA binding studied by atomistic molecular dynamics simulations

“…Using these approaches, reasonable values for the persistence length were obtained with the AMBER and CHARMM force fields [59,73], and certain sequence-dependent patterns could be discerned. In fact, reasonable agreement with certain trends in the persistence length could even be obtained from normal mode analysis of DNA in an implicit solvent [76], although the persistence length was systematically overestimated.…”