Free-energy calculations for semi-flexible macromolecules: Applications to DNA knotting and looping
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 problemmore »
- Authors:
-
- Department of Molecular and Cell Biology, University of Texas at Dallas, Richardson, Texas 75083 (United States)
- Hypnagogic Software, Vancouver, British Columbia V6K 1V6 (Canada)
- Department of Physics and Astronomy, University of Texas at Brownsville, Brownsville, Texas 78520 (United States)
- Publication Date:
- OSTI Identifier:
- 22415328
- Resource Type:
- Journal Article
- Journal Name:
- Journal of Chemical Physics
- Additional Journal Information:
- Journal Volume: 141; Journal Issue: 17; Other Information: (c) 2014 Author(s); Country of input: International Atomic Energy Agency (IAEA); Journal ID: ISSN 0021-9606
- Country of Publication:
- United States
- Language:
- English
- Subject:
- 37 INORGANIC, ORGANIC, PHYSICAL AND ANALYTICAL CHEMISTRY; ACCURACY; BIFURCATION; COMPARATIVE EVALUATIONS; DNA; FREE ENERGY; NORMAL-MODE ANALYSIS; RECOMBINATION
Citation Formats
Giovan, Stefan M., Scharein, Robert G., Hanke, Andreas, Levene, Stephen D., E-mail: sdlevene@utdallas.edu, Department of Bioengineering, University of Texas at Dallas, Richardson, Texas 75083, and Department of Physics, University of Texas at Dallas, Richardson, Texas 75083. Free-energy calculations for semi-flexible macromolecules: Applications to DNA knotting and looping. United States: N. p., 2014.
Web. doi:10.1063/1.4900657.
Giovan, Stefan M., Scharein, Robert G., Hanke, Andreas, Levene, Stephen D., E-mail: sdlevene@utdallas.edu, Department of Bioengineering, University of Texas at Dallas, Richardson, Texas 75083, & Department of Physics, University of Texas at Dallas, Richardson, Texas 75083. Free-energy calculations for semi-flexible macromolecules: Applications to DNA knotting and looping. United States. https://doi.org/10.1063/1.4900657
Giovan, Stefan M., Scharein, Robert G., Hanke, Andreas, Levene, Stephen D., E-mail: sdlevene@utdallas.edu, Department of Bioengineering, University of Texas at Dallas, Richardson, Texas 75083, and Department of Physics, University of Texas at Dallas, Richardson, Texas 75083. 2014.
"Free-energy calculations for semi-flexible macromolecules: Applications to DNA knotting and looping". United States. https://doi.org/10.1063/1.4900657.
@article{osti_22415328,
title = {Free-energy calculations for semi-flexible macromolecules: Applications to DNA knotting and looping},
author = {Giovan, Stefan M. and Scharein, Robert G. and Hanke, Andreas and Levene, Stephen D., E-mail: sdlevene@utdallas.edu and Department of Bioengineering, University of Texas at Dallas, Richardson, Texas 75083 and Department of Physics, University of Texas at Dallas, Richardson, Texas 75083},
abstractNote = {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.},
doi = {10.1063/1.4900657},
url = {https://www.osti.gov/biblio/22415328},
journal = {Journal of Chemical Physics},
issn = {0021-9606},
number = 17,
volume = 141,
place = {United States},
year = {Fri Nov 07 00:00:00 EST 2014},
month = {Fri Nov 07 00:00:00 EST 2014}
}