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.
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.
Weak nonbonded S···O interactions were characterized as stabilizing forces of protein structures based on the database analysis of selected heterogeneous structures in Protein Data Bank (PDB) as well as quantum chemical calculations at MP2/6-31G(d).
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