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Title: Free-energy calculations for semi-flexible macromolecules: Applications to DNA knotting and looping

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 » that arises naturally in gene regulation, DNA recombination, and the action of type-II topoisomerases.« less
Authors:
 [1] ;  [2] ;  [3] ;  [1] ;  [4] ;  [4]
  1. Department of Molecular and Cell Biology, University of Texas at Dallas, Richardson, Texas 75083 (United States)
  2. Hypnagogic Software, Vancouver, British Columbia V6K 1V6 (Canada)
  3. Department of Physics and Astronomy, University of Texas at Brownsville, Brownsville, Texas 78520 (United States)
  4. (United States)
Publication Date:
OSTI Identifier:
22415328
Resource Type:
Journal Article
Resource Relation:
Journal Name: Journal of Chemical Physics; Journal Volume: 141; Journal Issue: 17; Other Information: (c) 2014 Author(s); Country of input: International Atomic Energy Agency (IAEA)
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