CHSalign: A Web Server That Builds upon Junction-Explorer and RNAJAG for Pairwise Alignment of RNA Secondary Structures with Coaxial Helical Stacking

RESEARCH ARTICLE CHSalign: A Web Server That Builds upon Junction-Explorer and RNAJAG for Pairwise Alignment of RNA Secondary Structures with Coaxial Helical Stacking Lei Hua1☯, Yang Song1☯, Namhee Kim2, Christian Laing1, Jason T. L. Wang1*, Tamar Schlick2,3* 1 Bioinformatics Laboratory, Department of Computer Science, New Jersey Institute of Technology, Newark, New Jersey, United States of America, 2 Department of Chemistry, New York University, New York, New York, United States of America, 3 Courant Institute of Mathematical Sciences, New York University, New York, New York, United States of America ☯ These authors contributed equally to this work. * (JW); (TS) OPEN ACCESS Citation: Hua L, Song Y, Kim N, Laing C, Wang JTL, Schlick T (2016) CHSalign: A Web Server That Builds upon Junction-Explorer and RNAJAG for Pairwise Alignment of RNA Secondary Structures with Coaxial Helical Stacking. PLoS ONE 11(1): e0147097. doi:10.1371/journal.pone.0147097 Editor: Emanuele Paci, University of Leeds, UNITED KINGDOM Received: July 6, 2015 Accepted: December 29, 2015 Published: January 20, 2016 Copyright: © 2016 Hua et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Abstract RNA junctions are important structural elements of RNA molecules. They are formed when three or more helices come together in three-dimensional space. Recent studies have focused on the annotation and prediction of coaxial helical stacking (CHS) motifs within junctions. Here we exploit such predictions to develop an efficient alignment tool to handle RNA secondary structures with CHS motifs. Specifically, we build upon our JunctionExplorer software for predicting coaxial stacking and RNAJAG for modelling junction topologies as tree graphs to incorporate constrained tree matching and dynamic programming algorithms into a new method, called CHSalign, for aligning the secondary structures of RNA molecules containing CHS motifs. Thus, CHSalign is intended to be an efficient alignment tool for RNAs containing similar junctions. Experimental results based on thousands of alignments demonstrate that CHSalign can align two RNA secondary structures containing CHS motifs more accurately than other RNA secondary structure alignment tools. CHSalign yields a high score when aligning two RNA secondary structures with similar CHS motifs or helical arrangement patterns, and a low score otherwise. This new method has been implemented in a web server, and the program is also made freely available, at http://bioinformatics.njit.edu/CHSalign/. Data Availability Statement: All relevant data are within the paper and its Supporting Information files. Funding: This work was supported by National Science Foundation [grant IIS-0707571 to J.W.], and National Institute of General Medical Sciences [grants GM100469 and GM081410 to T.S.]. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. Introduction RNA secondary structures are composed of double-stranded segments such as helices connected to single-stranded regions such as junctions and hairpin loops. These structural elements serve as building blocks in the design of diverse RNA molecules with various functions PLOS ONE | DOI:10.1371/journal.pone.0147097 January 20, 2016 1 / 22 CHSalign Web Server in the cell [1–3]. In particular, RNA junctions are important structural elements due to their ability to orient many parts of the RNA molecule [4]. An RNA junction, also known as a multi-branch loop, forms when more than two helical segments are brought together [5–10]. RNA junctions exist in numerous RNA molecules; they play important roles in a wide variety of biochemical activities such as self-cleavage of the hammerhead ribozyme [11], the recognition of the binding pocket domain by purine riboswitches [12] and the translation initiation of the hepatitis C virus at the internal ribosome entry site [13]. Recent studies have classified RNA junctions with three and four branches into three and nine families, respectively [14,15]. Experiments have verified that a three-way junction in Arabidopsis has an important functional role [16]. A junction database, called RNAJunction, has been established, which contains junctions of all known degrees of branching [5]. A common tertiary motif within junctions of an RNA molecule is the coaxial stacking of helices [17–19], which occurs when two separate helical segments are aligned on a common axis to form a pseudocontiguous helix [20]. Coaxial stacking configurations have been observed in all large RNAs for which crystal structures are available, including tRNA, group I and II introns, RNase P, riboswitches and large ribosomal subunits. Coaxial helical stacking (CHS) provides thermodynamic stability to the RNA molecule as a whole [21] and reduces the separation between loop regions within junctions [22]. Moreover, coaxial stacking configurations form cooperatively with long-range interactions in many RNAs [14,17,23], and are therefore crucial as for correct tertiary structure formation as well as the formation of different junction topologies [15,17,24]. Since junctions are major architectural components in RNA, it is important to understand their structural properties. For example, the function of RNA molecules may be inferred if their junction components are similar in structure to other well-studied junction domains. In this paper we build upon our previously developed Junction-Explorer tool [25] for predicting coaxial stacking and RNAJAG [4] for modelling junction topologies as tree graphs, and present a method, CHSalign, for aligning two RNA secondary (2D) structures that possess CHS motifs within the junctions of the two RNA structures. Coaxial stacking interactions in junctions are part of tertiary (3D) motifs [24]. Thus, CHSalign differs from both RNA 2D and 3D structure alignment tools. Existing secondary (2D) structure alignment tools focus on sequences and base pairs without considering tertiary motifs. Existing tertiary (3D) structure alignment tools accept as input two RNA 3D structures including all types of tertiary motifs in the Protein Data Bank (PDB) [26] and align the 3D structures by considering their geometric properties, torsion angles, and base pairs. For 3D structure alignment, Ferre et al. [27] developed a dynamic programming algorithm based on nucleotide, dihedral angle, and base pairing similarities. Capriotti and Marti-Renom [28] developed a program to align two RNA 3D structures based on a unit-vector root-meansquare approach. Chang et al. [29] and Wang et al. [30] employed a structural alphabet of different nucleotide conformations to align RNA 3D structures. Hoksza and (...truncated)