Base pair opening within B-DNA: free energy pathways for GC and AT pairs from umbrella sampling simulations.

The conformational pathways and the free energy variations for base opening into the major and minor grooves of a B-DNA duplex are studied using umbrella sampling molecular dynamics simulations. We compare both GC and AT base pair opening within a double-stranded d(GAGAGAGAGAGAG)* d(CTCTCTCTCTCTC) oligomer, and we are also able to study the impact of opening on the conformational and dynamic properties of DNA and on the surrounding solvent. The results indicate a two-stage opening process with an initial coupling of the movements of the bases within the perturbed base pair. Major and minor groove pathways are energetically comparable in the case of the pyrimidine bases, but the major groove pathway is favored for the larger purine bases. Base opening is coupled to changes in specific backbone dihedrals and certain helical distortions, including untwisting and bending, although all these effects are dependent on the particular base involved. Partial opening also leads to well defined water bridging sites, which may play a role in stabilizing the perturbed base pairs.

[1]  Richard Lavery,et al.  Base flipping in DNA: pathways and energetics studied with molecular dynamic simulations. , 2002, Journal of the American Chemical Society.

[2]  Alexander D. MacKerell,et al.  Free energy and structural pathways of base flipping in a DNA GCGC containing sequence. , 2002, Journal of molecular biology.

[3]  R. Lavery,et al.  Energetic and conformational aspects of A:T base-pair opening within the DNA double helix. , 2001, Chemphyschem : a European journal of chemical physics and physical chemistry.

[4]  D. Beveridge,et al.  Molecular dynamics simulations of B '-DNA: sequence effects on A-tract-induced bending and flexibility. , 2001, Journal of molecular biology.

[5]  S. Volkov,et al.  Preopening of the DNA base pairs , 2001 .

[6]  Junmei Wang,et al.  How well does a restrained electrostatic potential (RESP) model perform in calculating conformational energies of organic and biological molecules? , 2000, J. Comput. Chem..

[7]  Alexander D. MacKerell,et al.  New insights into the structure of abasic DNA from molecular dynamics simulations , 2000, Nucleic Acids Res..

[8]  Alexander D. MacKerell,et al.  All‐atom empirical force field for nucleic acids: I. Parameter optimization based on small molecule and condensed phase macromolecular target data , 2000 .

[9]  Alexander D. MacKerell,et al.  All-atom empirical force field for nucleic acids: I. Parameter optimization based on small molecule and condensed phase macromolecular target data , 2000, J. Comput. Chem..

[10]  L. Joshua-Tor,et al.  A structural snapshot of base-pair opening in DNA. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[11]  U. Dornberger,et al.  High Base Pair Opening Rates in Tracts of GC Base Pairs* , 1999, The Journal of Biological Chemistry.

[12]  M Guéron,et al.  Determination of the residence time of water molecules hydrating B'- DNA and B-DNA, by one-dimensional zero-enhancement nuclear Overhauser effect spectroscopy. , 1999, Journal of molecular biology.

[13]  P. Kollman,et al.  A modified version of the Cornell et al. force field with improved sugar pucker phases and helical repeat. , 1999, Journal of biomolecular structure & dynamics.

[14]  D M Crothers,et al.  DNA curvature and deformation in protein-DNA complexes: a step in the right direction. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[15]  Effect of backbone ζ torsion angle on low energy single base opening in B-DNA crystal structures , 1998 .

[16]  R. Griffey,et al.  The opening of a single base without perturbations of neighboring nucleotides: a study on crystal B-DNA duplex d(CGCGAATTCGCG)2. , 1998, Journal of biomolecular structure & dynamics.

[17]  R. Lavery,et al.  Modelling base pair opening: the role of helical twist☆ , 1997 .

[18]  K Schulten,et al.  VMD: visual molecular dynamics. , 1996, Journal of molecular graphics.

[19]  B. Roux.  The calculation of the potential of mean force using computer simulations , 1995 .

[20]  P. Kollman,et al.  Molecular Dynamics Simulations on Solvated Biomolecular Systems: The Particle Mesh Ewald Method Leads to Stable Trajectories of DNA, RNA, and Proteins , 1995 .

[21]  M. Guéron,et al.  Studies of base pair kinetics by NMR measurement of proton exchange. , 1995, Methods in enzymology.

[22]  E. Folta-Stogniew,et al.  Sequence dependence of base-pair opening in a DNA dodecamer containing the CACA/GTGT sequence motif. , 1994, Biochemistry.

[23]  R. Roberts,et al.  Hhal methyltransferase flips its target base out of the DNA helix , 1994, Cell.

[24]  Molecular dynamics study of the base pair opening process in the self-complementary octanucleotide d(CTGATCAG). , 1993, Journal of biomolecular structure & dynamics.

[25]  T. Darden,et al.  Particle mesh Ewald: An N⋅log(N) method for Ewald sums in large systems , 1993 .

[26]  C. Brooks,et al.  Constant-temperature free energy surfaces for physical and chemical processes , 1993 .

[27]  R. Swendsen,et al.  THE weighted histogram analysis method for free‐energy calculations on biomolecules. I. The method , 1992 .

[28]  M. Guéron,et al.  Base-Pair Opening in Double-Stranded Nucleic Acids , 1992 .

[29]  J. Ramstein,et al.  Evidence for the stochastic nature of base pair opening in DNA: a Brownian dynamics simulation , 1991 .

[30]  C L Brooks,et al.  Reverse turns in blocked dipeptides are intrinsically unstable in water. , 1990, Journal of molecular biology.

[31]  J. Ramstein,et al.  Base pair opening pathways in B-DNA. , 1990, Journal of biomolecular structure & dynamics.

[32]  R. Lavery,et al.  Defining the structure of irregular nucleic acids: conventions and principles. , 1989, Journal of biomolecular structure & dynamics.

[33]  M. Guéron,et al.  Evidence from base-pair kinetics for two types of adenine tract structures in solution: their relation to DNA curvature. , 1988, Biochemistry.

[34]  J. Ramstein,et al.  Energetic coupling between DNA bending and base pair opening. , 1988, Proceedings of the National Academy of Sciences of the United States of America.

[35]  M. Guéron,et al.  A single mode of DNA base-pair opening drives imino proton exchange , 1987, Nature.

[36]  P. Kollman,et al.  Molecular mechanical studies of base‐pair opening in d(CGCGC):d(GCGCG), dG5·dC5, d(TATAT):d(ATATA), and dA5·dT5 in the B and Z forms of DNA , 1984 .

[37]  H. Berendsen,et al.  Molecular dynamics with coupling to an external bath , 1984 .

[38]  N. Kallenbach,et al.  Hydrogen exchange and structural dynamics of proteins and nucleic acids , 1983, Quarterly Reviews of Biophysics.

[39]  P. Kollman,et al.  Molecular mechanical studies of DNA flexibility: coupled backbone torsion angles and base-pair openings. , 1982, Proceedings of the National Academy of Sciences of the United States of America.

[40]  M Karplus,et al.  Dynamical theory of activated processes in globular proteins. , 1982, Proceedings of the National Academy of Sciences of the United States of America.

[41]  R. Lavery,et al.  Steric accessibility of reactive centers in B‐DNA , 1981 .

[42]  G. Ciccotti,et al.  Numerical Integration of the Cartesian Equations of Motion of a System with Constraints: Molecular Dynamics of n-Alkanes , 1977 .

[43]  G. Torrie,et al.  Nonphysical sampling distributions in Monte Carlo free-energy estimation: Umbrella sampling , 1977 .