Macromolecular halogen bonds Public Deposited

http://ir.library.oregonstate.edu/concern/graduate_thesis_or_dissertations/rx913s947

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  • The halogen bond is a non-covalent, stabilizing interaction analogous to a hydrogen bond in which an anisotropically polarized halogen atom interacts electrostatically with a Lewis base. Until very recently, the ability of halogens to form these stabilizing interactions in biological macromolecules was all but unknown, but examples of halogen bonding have now been observed in nucleic acids as well as protein complexes with hormones, drugs and inhibitors. The lack of recognition of and information about these interactions, however, hinders their utilization in the design of biological interactions. This thesis deals with work done to elucidate the capabilities and properties of halogen bonds in the context of biological macromolecules. Protein kinases are an important and well-studied class of drug targets for diseases such as cancer. Despite the prevalence of halogenated inhibitors and drugs targeted to protein kinases, however, halogen bonds have not generally been recognized and therefore utilized in the design of ligand binding interactions. The number of occurrences of halogen bonds between protein kinases and inhibitors observed in the crystal structures in the Protein Data Bank indicate the potential utility of the interaction in inhibitor and drug design. Further, their structures suggest a strategy for targeting halogen bond interaction sites by demonstrating that halogen bond acceptors offering concave surfaces present a more favorable profile to potential halogen bond donors. Halogen bonds are also able to direct the conformation of a biological molecule. In several competition experiments, halogen bonds were shown to out- compete classical hydrogen bonds to stabilize and direct the conformation of a DNA Holliday junction. For bromine X-bonds, the energy of stabilization was estimated to be 2 to 5 kcal/mol more than a classic hydrogen bond. The relative stabilization provided by interactions with fluorine, bromine, and iodine indicated that polarizable halogens (such as iodine and bromine) form highly stabilizing halogen bonds, whereas fluorine does not. The strengths of these interactions follow the order of halogen polarization (F < Br < I) and specify a range of interaction energies available to the halogen bond in a macromolecular context. Together, these observations of halogen bond occurrence and stabilization suggest that halogen bonds can be a powerful tool for the design of macromolecular interactions.
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  • description.provenance : Approved for entry into archive by Julie Kurtz(julie.kurtz@oregonstate.edu) on 2007-10-03T20:05:04Z (GMT) No. of bitstreams: 1 Voth_dissertation.pdf: 22666115 bytes, checksum: d406be742aae3c0fd04a00952ee22477 (MD5)
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