Nucleic Acids Research Advance Access published online on June 9, 2009
Nucleic Acids Research, doi:10.1093/nar/gkp475
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Computational Biology |
Using DNA mechanics to predict in vitro nucleosome positions and formation energies
1Department of Physics & Astronomy and BioMaPS Institute for Quantitative Biology, Rutgers University, 136 Frelinghuysen Road, Piscataway, NJ 08854, 2Department of Biochemistry, Molecular Biology, and Cell Biology, Northwestern University, 2153 Sheridan Road, Evanston, IL 60208, 3Department of Pharmacology, UMDNJ, Robert Wood Johnson Medical School, 675 Hoes Lane, Piscataway, NJ 08854 and 4Center for Studies in Physics and Biology, The Rockefeller University, 1230 York Avenue, New York, NY 10065, USA
*To whom correspondence should be addressed. Tel: +1 732 445 1387; Fax: +1 732 445 5958; Email: morozov{at}physics.rutgers.edu
Received February 6, 2009. Revised May 6, 2009. Accepted May 18, 2009.
In eukaryotic genomes, nucleosomes function to compact DNA and to regulate access to it both by simple physical occlusion and by providing the substrate for numerous covalent epigenetic tags. While competition with other DNA-binding factors and action of chromatin remodeling enzymes significantly affect nucleosome formation in vivo, nucleosome positions in vitro are determined by steric exclusion and sequence alone. We have developed a biophysical model, DNABEND, for the sequence dependence of DNA bending energies, and validated it against a collection of in vitro free energies of nucleosome formation and a set of in vitro nucleosome positions mapped at high resolution. We have also made a first ab initio prediction of nucleosomal DNA geometries, and checked its accuracy against the nucleosome crystal structure. We have used DNABEND to design both strong and weak histone- binding sequences, and measured the corresponding free energies of nucleosome formation. We find that DNABEND can successfully predict in vitro nucleosome positions and free energies, providing a physical explanation for the intrinsic sequence dependence of histone–DNA interactions.