title: Computational identification of RNA functional determinants by three-dimensional quantitative structure-activity relationships.
abstract: Anti-infection drugs target vital functions of infectious agents, including their ribosome and other essential non-coding RNAs. One of the reasons infectious agents become resistant to drugs is due to mutations that eliminate drug-binding affinity while maintaining vital elements. Identifying these elements is based on the determination of viable and lethal mutants and associated structures. However, determining the structure of enough mutants at high resolution is not always possible. Here, we introduce a new computational method, MC-3DQSAR, to determine the vital elements of target RNA structure from mutagenesis and available high-resolution data. We applied the method to further characterize the structural determinants of the bacterial 23S ribosomal RNA sarcin-ricin loop (SRL), as well as those of the lead-activated and hammerhead ribozymes. The method was accurate in confirming experimentally determined essential structural elements and predicting the viability of new SRL variants, which were either observed in bacteria or validated in bacterial growth assays. Our results indicate that MC-3DQSAR could be used systematically to evaluate the drug-target potentials of any RNA sites using current high-resolution structural data.
authors.affiliation: Institute for Research in Immunology and Cancer, Université de Montréal, PO Box 6128, Downtown Station, Montréal, Québec H3C 3J7, Canada Department of Computer Science and Operations Research, Université de Montréal, PO Box 6128, Downtown Station, Montréal, Québec H3C 3J7, Canada.
authors.forename: Marc-Frédérick
authors.initials: MF
authors.lastname: Blanchet
authors.affiliation: Institute for Research in Immunology and Cancer, Université de Montréal, PO Box 6128, Downtown Station, Montréal, Québec H3C 3J7, Canada Department of Computer Science and Operations Research, Université de Montréal, PO Box 6128, Downtown Station, Montréal, Québec H3C 3J7, Canada.
authors.forename: Karine
authors.initials: K
authors.lastname: St-Onge
authors.affiliation: Institute for Research in Immunology and Cancer, Université de Montréal, PO Box 6128, Downtown Station, Montréal, Québec H3C 3J7, Canada.
authors.forename: Véronique
authors.initials: V
authors.lastname: Lisi
authors.affiliation: Institute for Research in Immunology and Cancer, Université de Montréal, PO Box 6128, Downtown Station, Montréal, Québec H3C 3J7, Canada.
authors.forename: Julie
authors.initials: J
authors.lastname: Robitaille
authors.affiliation: Department of Computer Science and Operations Research, Université de Montréal, PO Box 6128, Downtown Station, Montréal, Québec H3C 3J7, Canada.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Hamel
authors.affiliation: Institute for Research in Immunology and Cancer, Université de Montréal, PO Box 6128, Downtown Station, Montréal, Québec H3C 3J7, Canada Department of Computer Science and Operations Research, Université de Montréal, PO Box 6128, Downtown Station, Montréal, Québec H3C 3J7, Canada major@iro.umontreal.ca.
authors.forename: François
authors.initials: F
authors.lastname: Major
mesh_terms: D019295:Computational Biology / Q000379:methods; D008958:Models, Molecular; D021281:Quantitative Structure-Activity Relationship; D012313:RNA / Q000737:chemistry*; D012329:RNA, Bacterial / Q000737:chemistry / Q000378:metabolism; D016337:RNA, Catalytic / Q000737:chemistry / Q000378:metabolism; D012338:RNA, Ribosomal, 23S / Q000737:chemistry / Q000378:metabolism
chemical_list: D012329:RNA, Bacterial; D016337:RNA, Catalytic; D012338:RNA, Ribosomal, 23S; C427204:hammerhead ribozyme; D012313:RNA