Nucleic Acids Research Advance Access published online on October 30, 2009
Nucleic Acids Research, doi:10.1093/nar/gkp892
© The Author(s) 2009. Published by Oxford University Press.
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.5/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
NNDB: the nearest neighbor parameter database for predicting stability of nucleic acid secondary structure
Douglas H. Turner1 and
David H. Mathews2,*
1Department of Chemistry and Center for RNA Biology, Box 0216, University of Rochester, Rochester, NY 14627-0216 and 2Department of Biochemistry and Biophysics and Center for RNA Biology, Box 712, University of Rochester Medical Center, Rochester, NY 14642, USA
*To whom correspondence should be addressed. Tel: +1 585 275 1734; Fax: +1 585 275 6007; Email: david_mathews{at}urmc.rochester.edu
Received August 17, 2009. Revised October 4, 2009. Accepted October 6, 2009.
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ABSTRACT
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The Nearest Neighbor Database (NNDB,
http://rna.urmc.rochester.edu/NNDB)
is a web-based resource for disseminating parameter sets for
predicting nucleic acid secondary structure stabilities. For
each set of parameters, the database includes the set of rules
with descriptive text, sequence-dependent parameters in plain
text and html, literature references to experiments and usage
tutorials. The initial release covers parameters for predicting
RNA folding free energy and enthalpy changes.
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INTRODUCTION
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Nearest neighbor approaches were developed to predict the folding
stabilities of nucleic acid secondary structures (
1). These
parameter sets utilize empirical rules, generally derived from
optical melting experimental data, as the basis of the predictions.
For RNA, rules exist for predicting both free energy and enthalpy
change of Watson–Crick helices, GU pairs and loops (
2–5).
Parameters for DNA have also been assembled for predicting Watson–Crick
pair free energy and enthalpy change and free energy changes
of loops (
6,
7). These parameter sets are the basis of computer
programs that predict low free energy secondary structures.
Such programs include Mfold/UnaFold (
8,
9), the Vienna RNA package
(
10), RNA structure (
2), RNAsoft (
11) and Sfold (
12). Additional
approaches that use statistical learning of parameters for RNA
folding have also used the rules from the nearest neighbor methods
and derived new parameter values (
13,
14).
Nearest neighbor parameter sets include both a set of rules, called either equations or features, for predicting stability and a set of parameter values used by the equations (14). For RNA, separate rules exist for predicting stabilities of helices, hairpin loops, small internal loops, large internal loops, bulge loops, multibranch loops, exterior loops and pseudoknots. Given the number of rules and constraints on the length of journal publications, it is difficult to assemble all the parameters in one publication and provide meaningful tutorials for using the parameters. This is a barrier to software development for novel algorithms that could take advantage of the parameters. For example, many software packages that use RNA parameters still implement the set of parameters assembled in 1999 (4), in spite of the fact the RNA parameters were updated in 2004 (2) based on experimental results.
The Nearest Neighbor Database (NNDB) is a web-based tool for assembling and archiving complete nearest neighbor sets, including rules and values. It is available online at http://rna.urmc.rochester.edu/NNDB. It provides documentation of parameter sets and tutorials on how to apply the parameters. Currently, the 1999 and 2004 sets of RNA folding parameters are provided (2–5).
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WEBSITE ORGANIZATION
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The NNDB is built using a set of static html, specifically XHTML
1.0 transitional pages with a page hierarchy shown in
Figure 1.
Text is encoded in Unicode (utf-8) to facilitate display of
equations in pages with diverse browsers running on diverse
operating systems. The top-level page provides access to a help
page, available parameter sets and a page of references to RNA
optical melting experiments. Additionally, links provide downloading
of the whole database in either zip or gzipped tar format. The
help page introduces the purpose of the database and defines
basic terms, including the set of structural features defined
by secondary structures. For example,
Figure 2, from the help
page, shows an RNA secondary structure that illustrates the
loop features covered by nearest neighbor parameter sets. The
basic equations for utilizing the parameters to extrapolate
folding free energy changes to temperatures other than 37°C
and to predict melting temperatures are also provided.
View larger version (17K):
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[Download PowerPoint slide]
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Figure 1. The webpage hierarchy of the NNDB. This figure illustrates the page hierarchy by following the linked pages down through the 1999 parameters and down to the hairpin loop pages. Note that there are five example calculations for hairpin loops to illustrate the separate sequence-dependent rules that are used depending on the specific loop.
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View larger version (19K):
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[in a new window]
[Download PowerPoint slide]
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Figure 2. An RNA secondary structure illustrating the types of features included in nearest neighbor parameter sets. This figure appears on the help page of the website. Loops are composed of nucleotides not in canonical pairs. Hairpin loops have one exiting helix. Internal and bulge loops have two exiting helices. Internal loops have nucleotides not in canonical pairs on each of two strands, but bulge loops have nucleotides not in canonical pairs on only one strand. Multibranch loops, also called helical junctions, have three or more exiting helices. Exterior loops contain the ends of sequences and one or more exiting helices. Pseudoknots are canonical pairs connecting loop regions closed by other helices. Formally, a pseudoknot occurs when there are at least two pairs, with indices i paired to j and i' paired to j', that satisfy the condition i < i' < j < j'. The pseudoknot helix is often considered to be composed of the fewest pairs that need to be removed to relieve the pseudoknot (19). In this structure, the tan nucleotides are in pairs that could be removed to relieve the pseudoknot.
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For each set of parameters, a first page introduces the available
parameters, which vary from set to set. For example, the 1999
RNA rules predict only folding free energy changes (
4), but
the 2004 rules can be used to predict both folding free energy
and enthalpy changes (
2,
5). For each structural feature, a page
defines the basic equations and provides links to parameter
values (in plain text and html), references and tutorial pages
(e.g.
Figure 3). The number of tutorials varies from feature
to feature; the set of tutorials is designed to cover each type
of rule that can be encountered in practice. For example, the
Watson–Crick helix parameters are covered with two tutorials,
one for self-complementary and one for non-self-complementary
strands. These two tutorials also demonstrate the difference
in the calculation when there are terminal AU base pairs, which
receive a free energy and enthalpy change penalty (
3), because
the self-complementary duplex example has two terminal AU pairs
and the non-self-complementary case has no terminal AU pairs.
The individual pages are designed for ease of navigation and
clarity. Individual pages above the level of value tables have
top banner, a left navigation bar that allows the user to navigate
back up the hierarchy to any level above and a bottom bar with
the date of last editing. For pages edited after the database
has gone online, previous versions of the page are available
using this bottom content bar. To facilitate indexing by search
engines, all pages have a descriptive title, including the set
of parameters to which it belongs (if applicable).
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WEBSITE CONTENT
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The first release of the NNDB contains the RNA folding rules
assembled in 1999 and 2004 (
2–5). These rules represent
the most recent set of parameters and a prior set that is widely
used in software packages. Because folding rules are derived
to work as a set, the two versions of rules and values should
not be mixed and the website hierarchy reinforces this.
The website is designed to be expandable to additional sets of parameters. It is anticipated, for example, that additional pages will be written to include nearest neighbors for DNA folding (6,7) and for predicting RNA pseudoknot stabilities (15–18). Additionally, the values derived from the re-estimation of the values of the 1999 parameter set using the set of known RNA secondary structures will also be included (14).
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DISCUSSION
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The NNDB is designed to provide a convenient location for assembling
parameter sets for predicting the stability of nucleic acid
secondary structures. It is modular in design, which facilitates
its future expansion to contain additional parameter sets. Furthermore,
the web format makes it feasible to provide extensive tutorials
for utilizing the parameters, which is generally not possible
in print.
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FUNDING
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The creation of the NNDB was supported by United States National
Institutes of Health grants GM076485 to D.H.M. and GM22939 to
D.H.T. Funding for open access charge: United States National
Institutes of Health.
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REFERENCES
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ABSTRACT
INTRODUCTION