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.
Highlights
2061-Pos Board B791 Free Energy Calculation of Protein Conformational Changes using Parallel Cascade Selection Molecular Dynamics Simulation and Markov State Model Yasutaka Nishihara1, Ryuhei Harada2, Akio Kitao1. 1University of Tokyo, Tokyo, Japan, 2RIKEN, Hyogo, Japan
Simulation of proteins and other large biomolecules rely on a force field representation of the potential energy surface
Fixed charge force fields, like AMBER, CHARMM, OPLS, and GROMOS, are widely used, it is well known that they, due to their simplicity provide an inaccurate description of the electrostatic energy component
Summary
2061-Pos Board B791 Free Energy Calculation of Protein Conformational Changes using Parallel Cascade Selection Molecular Dynamics Simulation and Markov State Model Yasutaka Nishihara1, Ryuhei Harada2, Akio Kitao1. 1University of Tokyo, Tokyo, Japan, 2RIKEN, Hyogo, Japan. 2057-Pos Board B787 Multipoles as Force Field Parameters - Accuracy and Redundancy Sofie Jakobsen. Simulation of proteins and other large biomolecules rely on a force field representation of the potential energy surface.
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