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Biennial Meeting Chemical Biology Group

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jordipoater

Flash communication given at the First Biennial Meeting of the Chemical Biology Group of the Real Sociedad Española de Química. Santiago de Compostela, 8-9 th March 2012.

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I meeting of the RSEQ Chemical Biology Group Santiago de Compostela - March 8 and 9, 2012 Real Sociedad Española de Química Role of Hydrogen Bonding, pi-Stacking and Solvation on Stacked DNA Base Pairs J. Poater, M. Swart, C. Fonseca Guerra and F. M. Bickelhaupt Institute of Computational Chemistry and Department of Chemistry, Universitat de Girona jordi.poater@udg.edu
Objectives of this work •  This is the first high-level quantum chemical study on DNA replication covering not only the formation of DNA base pairs but also π-π stacking interactions in a model system consisting of four DNA bases. •  Investigations on chemical primer extension, both computational (this work) and experimental, are relevant also for understanding the role of polymerase because they reveal how replication fidelity is affected in the absence of the enzyme.
Incoming nucleotide selectivity
H •  X + Y1/Z-Y2 → X-Y1/Z-Y2 N with X = A, T, G, C and F; and Y1/Z-Y2 = A/T-A, T/A-T, G/C-G H N TW and C/G-C.
•  Solvation leads to a general reduction of all affinities. Note however that this weakening is more pronounced for the G-C than for the A-T pair.
•  Stacking interactions appear to be important for the strength of the affinity of the template-primer complex but less so for the selectivity.
•  "nearest neighbor" effect: the affinity of the primer-template complex for the correct incoming DNA base depends on which DNA base is situated at the terminal position of the primer strand.
Conclusions •  The intrinsic affinity (i.e., in the absence of an enzyme) of the template-primer complex to select the correct natural DNA base derives from the cooperative action of hydrogen-bonding patterns and solvent effects. •  Stacking interactions play a less pronounced role for the selectivity but they are important for the overall stability. •  A primer strand with a purine terminus interacts more favorably with an incoming nucleotide than a primer strand with a pyrimidine base. •  The correct incorporation of nonpolar isosters, e.g., 1,3- difluorotoluene (F, an isoster of T), can not be explained without invoking an additional mechanism, such as, steric fit of the new base pair into the polymerase active-site pocket J. Poater, M. Swart, C. Fonseca-Guerra, F. M. Bickelhaupt, Chem. Comm. 2011, 47, 7326-7328.

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Biennial Meeting Chemical Biology Group

  • 1. I meeting of the RSEQ Chemical Biology Group Santiago de Compostela - March 8 and 9, 2012 Real Sociedad Española de Química Role of Hydrogen Bonding, pi-Stacking and Solvation on Stacked DNA Base Pairs J. Poater, M. Swart, C. Fonseca Guerra and F. M. Bickelhaupt Institute of Computational Chemistry and Department of Chemistry, Universitat de Girona jordi.poater@udg.edu
  • 2. Objectives of this work •  This is the first high-level quantum chemical study on DNA replication covering not only the formation of DNA base pairs but also Ï€-Ï€ stacking interactions in a model system consisting of four DNA bases. •  Investigations on chemical primer extension, both computational (this work) and experimental, are relevant also for understanding the role of polymerase because they reveal how replication fidelity is affected in the absence of the enzyme.
  • 4. H •  X + Y1/Z-Y2 → X-Y1/Z-Y2 N with X = A, T, G, C and F; and Y1/Z-Y2 = A/T-A, T/A-T, G/C-G H N TW and C/G-C.
  • 5. •  Solvation leads to a general reduction of all affinities. Note however that this weakening is more pronounced for the G-C than for the A-T pair.
  • 6. •  Stacking interactions appear to be important for the strength of the affinity of the template-primer complex but less so for the selectivity.
  • 7. •  "nearest neighbor" effect: the affinity of the primer-template complex for the correct incoming DNA base depends on which DNA base is situated at the terminal position of the primer strand.
  • 8. Conclusions •  The intrinsic affinity (i.e., in the absence of an enzyme) of the template-primer complex to select the correct natural DNA base derives from the cooperative action of hydrogen-bonding patterns and solvent effects. •  Stacking interactions play a less pronounced role for the selectivity but they are important for the overall stability. •  A primer strand with a purine terminus interacts more favorably with an incoming nucleotide than a primer strand with a pyrimidine base. •  The correct incorporation of nonpolar isosters, e.g., 1,3- difluorotoluene (F, an isoster of T), can not be explained without invoking an additional mechanism, such as, steric fit of the new base pair into the polymerase active-site pocket J. Poater, M. Swart, C. Fonseca-Guerra, F. M. Bickelhaupt, Chem. Comm. 2011, 47, 7326-7328.