Weak nonbonded interactions between a divalent sulfur (S) atom and a main-chain carbonyl oxygen (O) atom have recently been characterized in proteins. However, they have shown distinctly different directional propensities around the O atom from the S...O interactions in small organic compounds, although the linearity of the C-S...O or S-S...O atomic alignment was commonly observed. To elucidate the observed discrepancy, a comprehensive search for nonbonded S.O interactions in the Cambridge Structural Database (CSD) and MP2 calculations on the model complexes between dimethyl disulfide (CH(3)SSCH(3)) and various carbonyl compounds were performed. It was found that the O atom showed a strong intrinsic tendency to approach the S atom from the backside of the S-C or S-S bond (in the sigma(S) direction). On the other hand, the S atom had both possibilities of approach to the carbonyl O atom within the same plane (in the n(O) direction) and out of the plane (in the pi(O) direction). In the case of S...O(amide) interactions, the pi(O) direction was significantly preferred as observed in proteins. Thus, structural features of S...O interactions depend on the type of carbonyl groups involved. The results suggested that S.O interactions may control protein structures to some extent and that the unique directional properties of S...O interactions could be applied to molecular design.

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Sulfur-containing functional groups of cystine (an SSC group) and methionine (a CSC group) are usually considered as hydrophobic moieties or weak hydrogen-bond acceptors in folded protein structures. However, database analysis as well as theoretical calculations carried out in this study have provided strong evidence for the presence of specific nonbonded interactions between the divalent sulfur atoms (S) and nearby polar non-hydrogen atoms (X). Close S···X (X = O, N, S, C, etc.) atomic contacts were statistically analyzed in 604 high-resolution heterogeneous X-ray structures selected from a protein databank (PDB_SELECT). The S···O interactions found for both SSC and CSC groups showed a specific character as a π(C=O) → σ*(S) orbital interaction based on the directional preferences. The interactions were most frequently observed in α-helices. Ab initio calculations applying the second order Møller–Plesset perturbation theory (MP2) suggested the primary importance of electron correlations. The total stabilization energies were calculated to be ∼3.2 and ∼2.5 kcal/mol for SSC and CSC groups, respectively, including the contribution from a coexisting CH···O hydrogen bond. On the other hand, the S···N interactions observed for a CSC group exhibited structural characters as a π(N) → σ*(S) orbital interaction and an NH···S hydrogen bond, and the S···S interactions for an SSC group showed a structural character as an n(S) → σ*(S) orbital interaction. The S···C(π) interactions should be rather weak and long-range.

1H NMR analysis of seven 2-selenobenzylamine derivatives (ArSeX, 1−7) has revealed the existence of attractive nonbonded interaction between the divalent selenium and an unsymmetric amino nitrogen, whose strength significantly depends on the relative electrophilic reactivity of the selenium moiety. In the intermediate cases (5, X = CN; 6, X = SPh), the dissociation energy of the Se···N nonbonded interaction was evaluated as 12.4 and 10.8 kcal/mol, respectively, by variable-temperature 1H NMR spectral simulations. The corresponding values were roughly estimated as >18.8 kcal/mol for the strong cases (2, X = Br; 3, X = Cl; 4, X = OAc) and <7.7 kcal/mol for the weak cases (1, X = SeAr; 7, X = Me). In order to elucidate physicochemical properties of the interaction, 15N-labeled compounds were synthesized. Downfield shifts of 15N NMR (ΔδN) and increment of J Se···N (coupling constant between 77Se and 15N) were observed with increasing Se···N interaction. In the case of strong Se···N interaction, saturation of coupling constants was observed. These experimental observations as well as large NBO deletion energies (3-21G* and LANL1DZ) between the selenium and the nitrogen for model compounds (9−13) strongly suggested that the observed Se···N interaction is mainly caused by the orbital interaction between the nitrogen lone pair (nN) and the antibonding orbital of the Se−X bond (σ*Se-X).