Reference number : GC-2017-Q1-03352, amendment number : , agreement type : G, recipient legal name : Chalikian, Tigran (University of Toronto), recipient country : CA, recipient province : nan, recipient city : Ontario, recipient postal code : nan, program name english : Discovery Grants Program - Individual, program name french : Programme de subventions à la découverte - individuelles, program purpose english : We propose to continue our studies to characterize the thermodynamic content of the role of solvent in modulating the binding affinity and conformational preferences of biopolymers. During the previous budget period, our studies were focussed on investigating the role of water and water-soluble cosolvents in the energetics of protein and nucleic acid transitions and ligand-protein binding. In parallel, we have begun to establish a program in which we characterize the influence of solvent and individual solvent components on the energetics of DNA G-quadruplexes and i-motifs. G-quadruplexes and i-motifs form an important class of noncanonical tetrameric DNA structures of biological importance. Guanine-rich DNA strands are prone to fold into various G-quadruplex structures in which guanine bases associate with each other in stable hydrogen-bonded arrangements, G-quartets. Cytosine-rich strands exhibit a propensity to fold into the i-motif conformation at slightly acidic to near neutral pH. The latter represents a DNA conformation with a tetraplex arrangement of two parallel-stranded duplexes intercalated into each other in an antiparallel orientation. 
 
G-quadruplexes and i-motifs exhibit a great deal of diversity in topology and struc&not;ture which is believed to be of biological relevance. Subtle changes in nucleotide sequence, type of the stabilizing counterion, and the environmental conditions (e. g., presence of osmolytes or crow&not;ders) results in dramatic changes in the topology of a G-quadruplex. During the requested budget period, we propose to explore the role of water and water-miscible cosolvents (such as urea and glycine betaine) and the concentration of various cations and pH in guiding the polymorphic tendencies of noncanonical tetraplex DNA motifs. We have designed an experimental strategy aimed at developing a predictive algorithm that can be used to explore the conformational preferences of guanine-rich sequences as a function of environmental factors and the presence of their complementary cytosine-rich strands. We will employ differential scanning calorimetry, UV/Vis spectrophotometry, CD spectroscopy, ultrasonic velocimetry, and high precision densimetry. We already have demonstrated the feasibility and information content of these experimental methods. 
 
Our long-term objective is to develop predictive algorithms needed to evaluate sequence-specific, structure-specific, and solvent-specific conformational preferences of functionally important domains within naturally occurring nucleic acids. With the success in genomic sequence generation in an increasingly large number of organisms, such a capacity is becoming highly desirable. Ultimately, one would like to assess if local sequence domains in the genome that favor particular structural motifs correspond to functional sites of biological action or control., program purpose french : We propose to continue our studies to characterize the thermodynamic content of the role of solvent in modulating the binding affinity and conformational preferences of biopolymers. During the previous budget period, our studies were focussed on investigating the role of water and water-soluble cosolvents in the energetics of protein and nucleic acid transitions and ligand-protein binding. In parallel, we have begun to establish a program in which we characterize the influence of solvent and individual solvent components on the energetics of DNA G-quadruplexes and i-motifs. G-quadruplexes and i-motifs form an important class of noncanonical tetrameric DNA structures of biological importance. Guanine-rich DNA strands are prone to fold into various G-quadruplex structures in which guanine bases associate with each other in stable hydrogen-bonded arrangements, G-quartets. Cytosine-rich strands exhibit a propensity to fold into the i-motif conformation at slightly acidic to near neutral pH. The latter represents a DNA conformation with a tetraplex arrangement of two parallel-stranded duplexes intercalated into each other in an antiparallel orientation. 
 
G-quadruplexes and i-motifs exhibit a great deal of diversity in topology and struc&not;ture which is believed to be of biological relevance. Subtle changes in nucleotide sequence, type of the stabilizing counterion, and the environmental conditions (e. g., presence of osmolytes or crow&not;ders) results in dramatic changes in the topology of a G-quadruplex. During the requested budget period, we propose to explore the role of water and water-miscible cosolvents (such as urea and glycine betaine) and the concentration of various cations and pH in guiding the polymorphic tendencies of noncanonical tetraplex DNA motifs. We have designed an experimental strategy aimed at developing a predictive algorithm that can be used to explore the conformational preferences of guanine-rich sequences as a function of environmental factors and the presence of their complementary cytosine-rich strands. We will employ differential scanning calorimetry, UV/Vis spectrophotometry, CD spectroscopy, ultrasonic velocimetry, and high precision densimetry. We already have demonstrated the feasibility and information content of these experimental methods. 
 
Our long-term objective is to develop predictive algorithms needed to evaluate sequence-specific, structure-specific, and solvent-specific conformational preferences of functionally important domains within naturally occurring nucleic acids. With the success in genomic sequence generation in an increasingly large number of organisms, such a capacity is becoming highly desirable. Ultimately, one would like to assess if local sequence domains in the genome that favor particular structural motifs correspond to functional sites of biological action or control., agreement title english : Solvent-Modulated Energetics of Tetrameric DNA Polymorphism, agreement title french : Solvent-Modulated Energetics of Tetrameric DNA Polymorphism, agreement number : RGPIN, agreement value : 140000.0, agreement start date : 2017-05-10, agreement end date : nan, description english : nan, description french : nan, expected results english : nan, expected results french : nan, additional information english : Grant or Award spanning more than one fiscal year. (2017-2018 to 2022-2023), additional information french : Subvention ou bourse octroyée s'appliquant à plus d'un exercice financier. (2017-2018 à 2022-2023), owner organization : nserc-crsng, owner organization title : Natural Sciences and Engineering Research Council of Canada | Conseil de recherches en sciences naturelles et en génie du Canada