Interproton Coupling over Five Bonds ⁵J(H—C_α—C(O)—N—C_α—H) in the Peptide Moiety: The Importance of Specific Association Effects

An experimental and theoretical study is presented of the conformational and solvent dependencies of long-range H—H coupling constants ⁵J(H—C_α—C(O)—N—C_α—H) in compounds which model the peptide backbone. Molecular orbital results for Fermi contact coupling in cis- and trans-N-methylacetamides do not follow a conformational dependence of the homoallylic type; negative values are predicted for most out-of-plane orientations of the C_α—H bonds. In addition, the calculated values for ⁵J_HIH′^cis and ⁵J_HIH′^trans are of opposite signs in the planar conformation of cyclo-(Gly-Gly) and the boat conformation of cyclo-(Gly-Tyr). However, relative sign measurements show that these two coupling constants are of the same sign in cyclo(Gly-Tyr), and that both are positive in cyclo-(Gly-Phgly). The inclusion of five water molecules in the MO calculations for cis-N-methylacetamide and ten water molecules in association with cyclo-(Gly-Gly) led to both positive ⁵J_HIH′^cis and ⁵J_HIH′^trans. As a consequence, any applicability of the empirical relationship of ⁵J(H—C_α—C(O—N—C_α—H) to ϕ and ψ angles in peptides does not have any theoretical basis in the molecular oribtal theory for unhydrated amide bonds.