Nucleic Acids Research Advance Access published online on September 3, 2009
Nucleic Acids Research, doi:10.1093/nar/gkp718
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Methods Online |
A generalized conformational energy function of DNA derived from molecular dynamics simulations
1Intelligent Modeling Laboratory, The University of Tokyo, 2-11-16 Yayoi, Bunkyo-ku, Tokyo 113-8656, 2Agricultural Bioinformatics Research Unit and Department of Biotechnology, Graduate School of Agricultural and Life Sciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-8657, 3Computational Biology Group, Neutron Biology Research Center, Quantum Beam Science Directorate, 4Quantum Bioinformatics Team, Center for Computational Science and e-Systems, Japan Atomic Energy Agency, 8-1 Umemidai, Kizugawa, Kyoto 619-0215 and 5Department of Bioscience and Bioinformatics, Kyushu Institute of Technology, 680-4 Kawazu, Iizuka, Fukuoka 820-8502, Japan
*To whom correspondence should be addressed. Tel: +81-48-462-1111 (Ext. 3179); Fax: +81-48- 462-1625; Email: tterada{at}riken.jp
Received December 24, 2008. Accepted August 14, 2009.
Proteins recognize DNA sequences by two different mechanisms. The first is direct readout, in which recognition is mediated by direct interactions between the protein and the DNA bases. The second is indirect readout, which is caused by the dependence of conformation and the deformability of the DNA structure on the sequence. Various energy functions have been proposed to evaluate the contribution of indirect readout to the free-energy changes in complex formations. We developed a new generalized energy function to estimate the dependence of the deformability of DNA on the sequence. This function was derived from molecular dynamics simulations previously conducted on B-DNA dodecamers, each of which had one possible tetramer sequence embedded at its center. By taking the logarithm of the probability distribution function (PDF) for the base-step parameters of the central base-pair step of the tetramer, its ability to distinguish the native sequence from random ones was superior to that with the previous method that approximated the energy function in harmonic form. From a comparison of the energy profiles calculated with these two methods, we found that the harmonic approximation caused significant errors in the conformational energies of the tetramers that adopted multiple stable conformations.
Present addresses: Satoshi Yamasaki, Computational Biology Research Center (CBRC), National Institute of Advanced Industrial Science and Technology (AIST), 2-42 Aomi, Koto-ku, Tokyo 135-0064, Japan. Tohru Terada, Molecular Scale Team, Computational Science Research Program, RIKEN, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan.