MOLECULAR DYNAMICS SIMULATIONS OF METAL-CONTAINING MODIFIED PNA DUPLEXES

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Peptide nucleic acids (PNA) are synthetic analogs of DNA which contain the same nucleobases as those in DNA but in which the sugar phosphate is replaced by a structurally homomorphous pseudopeptide chain. PNA forms by Watson Crick basepairing duplexes that are homomorphous to DNA ones. PNA strands can bind to other PNA strands%2C to DNA and to RNA. The computer time requested in this application will be used to investigate metal-containing alternative base pairs that can be introduced in PNA. The pursuit of these alternative basepairs has biological relevance because it will provide information relevant to assess the potential of these basepairs to store information by using coordinative bonds instead of hydrogen bonds%2C in a manner similar to that of the genetic code. In addition, the new hybrid PNA-metal molecules have properties that can be used in molecular electronics applications. Major thrusts in molecular electronics are the discovery of new molecules with nanometer dimensions that can function as molecular wires or devices and of methods for assembly of these molecules in nanosize circuits. We have discovered that peptide nucleic acid (PNA)%2C a synthetic analog of DNA%2C can be used as scaffold for metal ions by substitution of nucleobases within PNA oligomers with ligands that confer high affinity for metal ions to the PNA duplexes. As a consequence, the modified duplexes are bridged by a combination of hydrogen and coordinative bonds. We use this strategy for the controlled assembly of nanostructures containing TM ions based on ligand-modified PNA helical duplexes. Our approach offers control over the type and position of metal ions incorporated in the duplexes and enables us to place TM ions at specific locations in 1-D structures and to create metal arrays of sizable length. The specific goal of this proposal is to use molecular dynamics simulations to explore the structure of metal-containing PNA duplexes. Recent molecular dynamics studies of PNA-PNA and PNA-DNA duplexes show that PNA strands maintain stable double helical structures. Simulations started with either A-DNA or B-DNA converged to PNA structures that were in good agreement with reported NMR and crystallographic observations. Initial coordinates for the nucleic acid scaffold will be obtained from a B-DNA canonical double-helix with the same sequence as P. The sugar-phosphate backbone will be replaced with the peptide backbone%2C according to the correspondence between the PNA and DNA atoms. The molecular dynamics software that we plan to use is AMBER. The force field parm94 will be complemented with previously determined parameters for the PNA backbone. Coordinates and charges for %5BPt(bypiridine)2%5D2%2B have already been obtained by students in our lab using Gaussian98 with the B3LYP hybrid functional and the standard LANL2DZ basis set. Charges for PNA atoms were also already obtained using an HF%2F6-31G%2A basis set. We are requesting a starting grant of 30%2C000 service units on ben to initiate the simulations and obtain benchmarks.