Nucleic Acids Research Advance Access first published online on October 22, 2009
This version published online on November 6, 2009
Nucleic Acids Research, doi:10.1093/nar/gkp834
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Structural Biology |
A systematic molecular dynamics study of nearest-neighbor effects on base pair and base pair step conformations and fluctuations in B-DNA
1Institut de Biologie et Chimie des Protéines, CNRS UMR 5086/Université de Lyon, 7 passage du Vercors, 69367 Lyon, France, 2Department of Chemistry, Wesleyan University, Middletown, CT 06459, 3Center for Computational Science, Tulane University, Lindy Boggs Building Suite 500, New Orleans, LA 70118, 4BioMaPS Institute and Dept. of Chemistry & Chemical Biology, Rutgers University, 610 Taylor Road, Piscataway, NJ 08854-8087, 5Department of Pharmaceutics, University of Utah, SH 201, Salt Lake City, UT 84112, USA, 6Zymeworks Inc., 540-1385 W 8th Ave, Vancouver, BC V6H 3V9, Canada, 7Department of Chemistry, Indian Institute of Technology, Hauz Khas, New Delhi 110016, India, 8Center for Complex Molecular Systems and Biomolecules, Institute of Organic Chemistry and Biochemistry, Flemingovo nam. 2, 166 10 Praha 6, Czech Republic, 9Centre for Biomolecular Sciences, School of Pharmacy, University of Nottingham, NG7 2RD, UK, 10Institut de Mathématiques, Swiss Federal Institute of Technology, CH-1015 Lausanne, Switzerland, 11Department of Structural and Chemical Biology, Mount Sinai School of Medicine, New York, NY 10029, USA, 12Joint IRB-BSC Program on Computational Biology, Institute of Research in Biomedicine, Parc Científic de Barcelona, Josep Samitier 1-5, Barcelona 08028. Spain and Barcelona Supercomputing Centre, Jordi Girona 31, Edifici Torre Girona. Barcelona 08034, and Departament de Bioquímica, Facultat de Biología, Avgda Diagonal 647, Barcelona 08028, Spain and 13Institute of Biophysics, Academy of Sciences of the Czech Republic, Kralovopolska 135, 612 65 Brno, Czech Republic
*To whom correspondence should be addressed. Tel: +33 4 72 72 26 37; Fax: +33 4 72 72 26 04; Email: richard.lavery{at}ibcp.fr
Received August 17, 2009. Revised September 15, 2009. Accepted September 18, 2009.
It is well recognized that base sequence exerts a significant influence on the properties of DNA and plays a significant role in protein–DNA interactions vital for cellular processes. Understanding and predicting base sequence effects requires an extensive structural and dynamic dataset which is currently unavailable from experiment. A consortium of laboratories was consequently formed to obtain this information using molecular simulations. This article describes results providing information not only on all 10 unique base pair steps, but also on all possible nearest-neighbor effects on these steps. These results are derived from simulations of 50–100 ns on 39 different DNA oligomers in explicit solvent and using a physiological salt concentration. We demonstrate that the simulations are converged in terms of helical and backbone parameters. The results show that nearest-neighbor effects on base pair steps are very significant, implying that dinucleotide models are insufficient for predicting sequence-dependent behavior. Flanking base sequences can notably lead to base pair step parameters in dynamic equilibrium between two conformational sub-states. Although this study only provides limited data on next-nearest-neighbor effects, we suggest that such effects should be analyzed before attempting to predict the sequence-dependent behavior of DNA.
The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors.