title: On the Applicability of Elastic Network Models for the Study of RNA CUG Trinucleotide Repeat Overexpansion.
abstract: Non-coding RNAs play a pivotal role in a number of diseases promoting an aberrant sequestration of nuclear RNA-binding proteins. In the particular case of myotonic dystrophy type 1 (DM1), a multisystemic autosomal dominant disease, the formation of large non-coding CUG repeats set up long-tract hairpins able to bind muscleblind-like proteins (MBNL), which trigger the deregulation of several splicing events such as cardiac troponin T (cTNT) and insulin receptor's, among others. Evidence suggests that conformational changes in RNA are determinant for the recognition and binding of splicing proteins, molecular modeling simulations can attempt to shed light on the structural diversity of CUG repeats and to understand their pathogenic mechanisms. Molecular dynamics (MD) are widely used to obtain accurate results at atomistic level, despite being very time consuming, and they contrast with fast but simplified coarse-grained methods such as Elastic Network Model (ENM). In this paper, we assess the application of ENM (traditionally applied on proteins) for studying the conformational space of CUG repeats and compare it to conventional and accelerated MD conformational sampling. Overall, the results provided here reveal that ANM can provide useful insights into dynamic rCUG structures at a global level, and that their dynamics depend on both backbone and nucleobase fluctuations. On the other hand, ANM fail to describe local U-U dynamics of the rCUG system, which require more computationally expensive methods such as MD. Given that several limitations are inherent to both methods, we discuss here the usefulness of the current theoretical approaches for studying highly dynamic RNA systems such as CUG trinucleotide repeat overexpansions.
authors.affiliation: Grup d'Enginyeria Molecular (GEM), Institut Químic de Sarrià (IQS) - Universitat Ramon Llull (URL), Barcelona, Catalonia, 08017, Spain.
authors.forename: Àlex L
authors.initials: ÀL
authors.lastname: González
authors.affiliation: Grup d'Enginyeria Molecular (GEM), Institut Químic de Sarrià (IQS) - Universitat Ramon Llull (URL), Barcelona, Catalonia, 08017, Spain.
authors.forename: Jordi
authors.initials: J
authors.lastname: Teixidó
authors.affiliation: Grup d'Enginyeria Molecular (GEM), Institut Químic de Sarrià (IQS) - Universitat Ramon Llull (URL), Barcelona, Catalonia, 08017, Spain.
authors.forename: José I
authors.initials: JI
authors.lastname: Borrell
authors.affiliation: Grup d'Enginyeria Molecular (GEM), Institut Químic de Sarrià (IQS) - Universitat Ramon Llull (URL), Barcelona, Catalonia, 08017, Spain.
authors.forename: Roger
authors.initials: R
authors.lastname: Estrada-Tejedor
mesh_terms: D006801:Humans; D056004:Molecular Dynamics Simulation; D009223:Myotonic Dystrophy / Q000235:genetics; D009690:Nucleic Acid Conformation; D022661:RNA, Untranslated / Q000737:chemistry* / Q000235:genetics; D019680:Trinucleotide Repeat Expansion
chemical_list: D022661:RNA, Untranslated