Characterizing the Cooperativity in H-Bonded Amino Structures ² Tanja van Mourik* ,#,§ and Andrew J. Dingley ‡,£ Chemistry Department, UniVersity College London, 20 Gordon Street, London WC1H 0AJ, U.K., School of Chemistry, UniVersity of St. Andrews, North Haugh, St. Andrews, Fife, KY16 9ST, Scotland, U.K., Department of Biochemistry and Molecular Biology, UniVersity College London, Gower Street, London WC1E 6BT, U.K., and Department of Chemistry, The UniVersity of Auckland, Auckland, New Zealand ReceiVed: March 26, 2007; In Final Form: May 24, 2007 Density functional theory calculations were used to examine the effect of H-bond cooperativity on the magnitude of the NMR chemical shifts and spin-spin coupling constants in a C 4h -symmetric G-quartet and in structures consisting of six cyanamide monomers. These included two ring structures (a planar C 6h -symmetric structure and a nonplanar S 6 -symmetric structure) and two linear chain structures (a fully optimized planar C s -symmetric chain and a planar chain structure where all intra- and intermolecular parameters were constrained to be identical). The NMR parameters were computed for the G-quartet and cyanamide structures, as well as for shorter fragments derived from these assemblies without reoptimization. In the ring structures and the chain with identical monomers, the intra- and intermolecular geometries of the cyanamides were identical, thereby allowing the study of cooperative effects in the absence of geometry changes. The magnitude of the | 1 J NH | coupling, 1 H and 15 N chemical shifts of the H-bonding amino N-H group, and the | h2 J NN | H-bond coupling increased, whereas the size of the | 1 J NH | coupling of the non-H-bonded amino N-H bonds of the first amino group in the chain, which are roughly perpendicular to the H-bonding network, decreased in magnitude when H-bonding monomers were progressively added to extending ring or chain structures. These effects are attributed to electron redistribution induced by the presence of the nearby H-bonding guanine or cyanamide molecules. 1. Introduction Hydrogen bond (H-bond) interactions are often treated using pairwise energy potentials, which do not properly account for the cooperative nature of H-bonding interactions, yet such cooperativity is a key biological process in biomacromolecular folding and stability. Cooperative interactions in H-bonded assemblies are defined as the difference between the total interaction energy of a H-bonding chain of molecules and the sum of the pairwise H-bonding interaction energies. Various molecular properties are influenced by cooperativity effects, including geometric and vibrational properties. 1-3 Theoretical investigations examining H-bond cooperativity in peptides, formamide chains, and chains of HCN and HNC molecules have provided valuable data on cooperativity effects in H-bonded assemblies. 2-8 For example, in formamide chains, the central H-bonds were calculated to be significantly stronger than those located at the ends, and this effect increased as the chain length increased. 5 The experimental observation of spin-spin coupling constants between nuclei across the H-bond in chemical and biological systems 9-35 provides a direct approach for identifying the presence of H-bonds. These initial discoveries have led to numerous experimental and theoretical studies examining the character of the H-bonds in various chemical and biological molecules. 36 Since spin-spin couplings are exquisitely sensitive to structural changes, H-bond couplings (HBC) provide an ideal probe for exploring H-bond geometric properties and cooper- ativity in H-bonded systems. Recent density functional theory (DFT) and ab initio molecular orbital methods examining N-H‚‚‚OdC, N-H‚‚‚N, N-H‚‚‚C, and C-H‚‚‚N moieties have shown correlations between H-bond geometry and HBCs. 37-48 In addition, calculations have investigated H-bond cooperativity effects in which the H-bond geometries are identical between H-bonding moieties yet the size of the HBCs differ throughout the H-bonding chain. 49 Experimental research by Juranic ´ and co-workers 50,51 has shown that HBCs are sensitive to the extended environment of a H-bonded system and have provided correlations between intramolecular and intermolecular spin-spin couplings in a protein backbone context. DNA quadruplexes form tandem repeats of short guanine- rich sequences found in telomeres and are recognized to play important biological roles, interact with a number of proteins, and pose as potential therapeutic targets against cancer. The guanine quartet (G-quartet) structural motif found in quadru- plexes is characterized by four in-plane guanine bases hydrogen bonded together in a cyclic arrangement which is stabilized by the presence of monovalent ions such as K + and Na + . In a recent DFT study, we performed theoretical calculations of NMR parameters related to the (H)N-H‚‚‚N and N-H‚‚‚OdC H-bond moieties found in G-quartets and showed that the sizes of the two- ( h2 J NN ) and three-bond ( h3 J NC’ ) HBCs were correlated with various geometric features of the H-bonds. 47 Further DFT investigation of the amino group in cyanamide models and G-quartets revealed that H-bonding and consequent electron redistribution induced by the presence of the H-bond acceptor molecule are responsible for the calculated distance dependen- ² Part of the “Thom H. Dunning, Jr., Festschrift”. # University College London and University of St. Andrews. ‡ University College London and University of Auckland. § Current address: School of Chemistry, University of St. Andrews, North Haugh, St. Andrews, Fife, KY16 9ST, Scotland, UK. E-mail: tanja.vanmourik@st-andrews.ac.uk. £ Current address: Department of Chemistry, The University of Auck- land, Auckland, New Zealand. E-mail: a.dingley@auckland.ac.nz. 11350 J. Phys. Chem. A 2007, 111, 11350-11358 10.1021/jp072379i CCC: $37.00 © 2007 American Chemical Society Published on Web 08/04/2007