cgDNA: a software package for the prediction of sequence-dependent coarse-grain free energies of B-form DNA

Abstract

cgDNA is a package for the prediction of sequence-dependent configuration-space free energies for B-form DNA at the coarse-grain level of rigid bases. For a fragment of any given length and sequence, cgDNA calculates the configuration of the associated free energy minimizer, i.e. the relative positions and orientations of each base, along with a stiffness matrix, which together govern differences in free energies. The model predicts non-local (i.e. beyond base-pair step) sequence dependence of the free energy minimizer. Configurations can be input or output in either the Curves+ definition of the usual helical DNA structural variables, or as a PDB file of coordinates of base atoms. We illustrate the cgDNA package by comparing predictions of free energy minimizers from (a) the cgDNA model, (b) time-averaged atomistic molecular dynamics (or MD) simulations, and (c) NMR or X-ray experimental observation, for (i) the Dickerson–Drew dodecamer and (ii) three oligomers containing A-tracts. The cgDNA predictions are rather close to those of the MD simulations, but many orders of magnitude faster to compute. Both the cgDNA and MD predictions are in reasonable agreement with the available experimental data. Our conclusion is that cgDNA can serve as a highly efficient tool for studying structural variations in B-form DNA over a wide range of sequences.

Multiscale simulation of DNA

“…We will limit ourselves here to the latest (from 2013) advances in particle-based CG methods, both those oriented towards the study of DNA in biological context [124•-133], and those designed for nanocomposites (see the recent revisions of Yingling et al [134] and Ouldridge [135] [142] have been used in both fields. Despite the particle-based CG models reviewed here, it is worth to note the effort done by the community to build models at the interface of atomistic and coarse grain modeling, like the ones based on the flexibility of DNA bases considered as independent interacting rigid bodies where the ground state and the stiffness matrixes are taken from MD simulations [143,144], or the works done by Rohs and coworkers that used atomistic MC (Monte Carlo) simulations to derive a method for high-throughput DNA shape predictions [145][146][147].…”

Absolute versus Relative Entropy Parameter Estimation in a Coarse-Grain Model of DNA

“…Later we will see how the oligomer-based models from those sections can be used to parameterize the model presented here. For more details see [13], and for descriptions of associated software and various experimental verifications see [27,32].…”

“…Moreover, notice that this energy makes two additional and logically independent assumptions of locality in sequence, and independence of location along the oligomer, for example proximity to an end. In principle, larger parameter sets could be adopted with, for example, tetranucleotide sequence dependence of the junction energy parameters, but the examples presented in [13,32] suggest that the level of generality outlined above already provides a rather good approximation. One could also simplify to a sequence-independent model in which the parameters µ α , K α , µ αβ , and K αβ are independent of the labels α, β ∈ {T, A, C, G}.…”

“…Associated software and examples are described in [27,32]. In particular, the computational effort associated with applying the cgDNA model to a new sequence is far less than that required in an additional MD simulation for each sequence of interest, so that studies of much larger ranges in both length scales and sequence variation become feasible.…”

“…Similarly, the relative rotation and displacement between the base pairs (X, X) a and (X, X) a+1 along the strands is described in the associated junction frame by an inter -base-pair (Cayley or Gibbs) coordinate vector z a ∈ R 6 with entries comprising three rotation coordinates (Tilt-Roll-Twist) and three displacement coordinates (Shift-Slide-Rise), as illustrated in Figure 4. For an oligomer of n base pairs, there are a total of n intra-base-pair coordinate vectors y a , and a total of n − 1 inter-base-pair coordinate vectors z a , and the collection of all coordinates is denoted by (18) w We will use the specific nondimensional and scaled version of the above coordinates that is fully described in either [13] or [32], which includes an energy scale such that the Boltzmann factor k B T is equal to unity. Notice that the complete configuration of a DNA oligomer is specified by introducing a vector z 0 of six additional coordinates that specify the position and orientation of the oligomer with respect to an external, lab-fixed frame.…”