Free-Energy Calculations for Semi-Flexible Macromolecules: Applications to DNA Knotting and Looping

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Free-Energy Calculations for Semi-Flexible Macromolecules: Applications to DNA Knotting and Looping

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Title: Free-Energy Calculations for Semi-Flexible Macromolecules: Applications to DNA Knotting and Looping
Author(s):
Giovan, Stefan M. (UT Dallas);
Scharein, Robert G.;
Hanke, Andreas;
Levene, Stephen D. (UT Dallas)
Item Type: Article
Keywords: Free energy
Base pairs
DNA
Abstract: We present a method to obtain numerically accurate values of configurational free energies of semiflexible macromolecular systems, based on the technique of thermodynamic integration combined with normal-mode analysis of a reference system subject to harmonic constraints. Compared with previous free-energy calculations that depend on a reference state, our approach introduces two innovations, namely, the use of internal coordinates to constrain the reference states and the ability to freely select these reference states. As a consequence, it is possible to explore systems that undergo substantially larger fluctuations than those considered in previous calculations, including semiflexible biopolymers having arbitrary ratios of contour length L to persistence length P. To validate the method, high accuracy is demonstrated for free energies of prime DNA knots with L/P = 20 and L/P = 40, corresponding to DNA lengths of 3000 and 6000 base pairs, respectively. We then apply the method to study the free-energy landscape for a model of a synaptic nucleoprotein complex containing a pair of looped domains, revealing a bifurcation in the location of optimal synapse (crossover) sites. This transition is relevant to target-site selection by DNA-binding proteins that occupy multiple DNA sites separated by large linear distances along the genome, a problem that arises naturally in gene regulation, DNA recombination, and the action of type-II topoisomerases.;
Publisher: American Institute of Physics
ISSN: 1089-7690
Persistent Link: http://hdl.handle.net/10735.1/4228
http://dx.doi.org/10.1063/1.4900657
Terms of Use: CC-BY 3.0 (Attribution)
©2014 The Authors
Sponsors: US National Science Foundation/ (no. DMS-0800929); US National Institutes of Health (no. 2SC3GM083779-04A1)

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CC-BY 3.0 (Attribution) Except where otherwise noted, this item's license is described as CC-BY 3.0 (Attribution)