DNA and RNA exhibit an amazing degree of conformational heterogeneity, a property that is essential for their wide variety of biological functions, including replication and gene regulation. The importance of this heterogeneity in the biological functions of oligonucleotides is becoming more evident as more non-canonical structures that play essential roles in both eukaryotic and prokaryotic organisms are identified. The variety of conformations assumed by oligonucleotides, be they either canonical or non-canonical, is dictated by a balance between interactions with their environment, including interactions with other nucleic acids, proteins and small molecules, and of their intrinsic conformational properties. In the proposed study this balance will be investigated at an atomic level of detail using a combination of quantum mechanical (QM) and molecular dynamics (MD) based theoretical calculations. Towards this goal, further development of empirical force fields for nucleic acids will be undertaken, focusing on improvements in the currently available CHARMM27 additive model and the development of a next-generation polarizable force field based on the classical Drude oscillator and novel Lennard-Jones combining rules. QM studies of base stacking and the impact of the 2'OH in RNA on its conformational flexibility will yield improved understanding of the intrinsic determinants of DNA and RNA conformational heterogeneity as well as facilitate force field development. MD simulation studies on a range of canonical and non-canonical DNA and RNA structures will be used to validate the proposed force fields. MD simulations will also be applied to understand the dielectric environment of DNA and RNA based on calculation of the vibrational Stark effect and on solution conformations of DNA via calculation of solution X- ray diffraction and NMR spectra. The proposed force fields will also be applied to problems of medical relevance including novel gene therapy agents based on triplex forming oligonucleotides that target a wider range of DNA sequences and the impact of structural and dynamical perturbations in DNA on replication due to arylamine modifications of DNA associated with environmental toxins. Overall, the proposed studies will lead to more accurate empirical force fields for nucleic acids that will be of utility to a large number of workers in computational chemistry and biophysics as well as lead to improved understanding of atomic determinants of oligonucleotide conformational heterogeneity. The proposed force fields will also be use to facilitate the design of novel gene therapy agents and understand the impact of environmental carcinogens on DNA replication.

Public Health Relevance

Proposed improvements in the theoretical force fields used to investigate the structural and dynamical properties of DNA and RNA will allow for novel insights into the relationship of those properties to their many biological functions to be achieved. The improved force fields will then be used to develop new agents for use in gene therapy and to understand the impact of environmental toxins on DNA and how they adversely affect DNA replication, thereby leading to cancer.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM051501-17
Application #
8628840
Study Section
Macromolecular Structure and Function D Study Section (MSFD)
Program Officer
Preusch, Peter C
Project Start
1996-09-01
Project End
2015-02-28
Budget Start
2014-03-01
Budget End
2015-02-28
Support Year
17
Fiscal Year
2014
Total Cost
$266,667
Indirect Cost
$88,889
Name
University of Maryland Baltimore
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
188435911
City
Baltimore
State
MD
Country
United States
Zip Code
21201
Patel, Dhilon S; He, Xibing; MacKerell Jr, Alexander D (2015) Polarizable empirical force field for hexopyranose monosaccharides based on the classical Drude oscillator. J Phys Chem B 119:637-52
Vanommeslaeghe, K; MacKerell Jr, A D (2015) CHARMM additive and polarizable force fields for biophysics and computer-aided drug design. Biochim Biophys Acta 1850:861-71
Savelyev, Alexey; MacKerell Jr, Alexander D (2014) All-atom polarizable force field for DNA based on the classical Drude oscillator model. J Comput Chem 35:1219-39
Patel, Dhilon S; Pendrill, Robert; Mallajosyula, Sairam S et al. (2014) Conformational properties of ?- or ?-(1?6)-linked oligosaccharides: Hamiltonian replica exchange MD simulations and NMR experiments. J Phys Chem B 118:2851-71
Lakkaraju, Sirish Kaushik; Xue, Fengtian; Faden, Alan I et al. (2013) Estimation of ligand efficacies of metabotropic glutamate receptors from conformational forces obtained from molecular dynamics simulations. J Chem Inf Model 53:1337-49
Huang, Jing; MacKerell Jr, Alexander D (2013) CHARMM36 all-atom additive protein force field: validation based on comparison to NMR data. J Comput Chem 34:2135-45
Shim, Jihyun; Zhu, Xiao; Best, Robert B et al. (2013) (Ala)(4)-X-(Ala)4 as a model system for the optimization of the ýý1 and ýý2 amino acid side-chain dihedral empirical force field parameters. J Comput Chem 34:593-603
Lin, Bin; Lopes, Pedro E M; Roux, Benoît et al. (2013) Kirkwood-Buff analysis of aqueous N-methylacetamide and acetamide solutions modeled by the CHARMM additive and Drude polarizable force fields. J Chem Phys 139:084509
McDonald, Ashley Ringer; Denning, Elizabeth J; MacKerell Jr, Alexander D (2013) Impact of geometry optimization on base-base stacking interaction energies in the canonical A- and B-forms of DNA. J Phys Chem A 117:1560-8
Jain, Vipin; Hilton, Benjamin; Lin, Bin et al. (2013) Unusual sequence effects on nucleotide excision repair of arylamine lesions: DNA bending/distortion as a primary recognition factor. Nucleic Acids Res 41:869-80

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