Evidence for a strong sulfur-aromatic interaction derived from crystallographic data

Abstract

We have uncovered new evidence for a significant interaction between divalent sulfur atoms and aromatic rings. Our study involves a statistical analysis of interatomic distances and other geometric descriptors derived from entries in the Cambridge Crystallographic Database (F. H. Allen and O. Kennard, Chem. Design Auto. News, 1993, Vol. 8, pp. 1 and 31–37). A set of descriptors was defined sufficient in number and type so as to elucidate completely the preferred geometry of interaction between six‐membered aromatic carbon rings and divalent sulfurs for all crystal structures of nonmetal‐bearing organic compounds present in the database. In order to test statistical significance, analogous probability distributions for the interaction of the moiety X–CH2–X with aromatic rings were computed, and taken a priori to correspond to the null hypothesis of no significant interaction. Tests of significance were carried our pairwise between probability distributions of sulfur–aromatic interaction descriptors and their CH2–aromatic analogues using the Smirnov–Kolmogorov nonparametric test (W. W. Daniel, Applied Nonparametric Statistics, Houghton‐Mifflin: Boston, New York, 1978, pp. 276–286), and in all cases significance at the 99% confidence level or better was observed. Local maxima of the probability distributions were used to define a preferred geometry of interaction between the divalent sulfur moiety and the aromatic ring. Molecular mechanics studies were performed in an effort to better understand the physical basis of the interaction. This study confirms observations based on statistics of interaction of amino acids in protein crystal structures (R. S. Morgan, C. E. Tatsch, R. H. Gushard, J. M. McAdon, and P. K. Warme, International Journal of Peptide Protein Research, 1978, Vol. 11, pp. 209–217; R. S. Morgan and J. M. McAdon, International Journal of Peptide Protein Research, 1980, Vol. 15, pp. 177–180; K. S. C. Reid, P. F. Lindley, and J. M. Thornton, FEBS Letters, 1985, Vol. 190, pp. 209–213), as well as studies involving molecular mechanics (G. Nemethy and H. A. Scheraga, Biochemistry and Biophysics Research Communications, 1981, Vol. 98, pp. 482–487) and quantum chemical calculations (B. V. Cheney, M. W. Schulz, and J. Cheney, Biochimica Biophysica Acta, 1989, Vol. 996, pp.116–124; J. Pranata, Bioorganic Chemistry, 1997, Vol. 25, pp. 213–219)—all of which point to the possible importance of the sulfur–aromatic interaction. However, the preferred geometry of the interaction, as determined from our analysis of the small‐molecule crystal data, differs significantly from that found by other approaches. © 2000 John Wiley & Sons, Inc. Biopoly 53: 233–248, 2000

Structural Studies of a Potent Insect Maturation Inhibitor Bound to the Juvenile Hormone Esterase ofManduca sexta,

“…For example, an interaction between sulfur and the face of the phenylalanine benzene ring has been reported to be favored in some studies (59) and unfavored in others (35,37). Tauer et al (59) modeled interactions of H 2 S with benzene and reported that the optimal intermonomer distance was 3.8 Å with an interaction energy of -2.81 kcal mol −1 .…”

“…However, given that sulfur has a low electronegativity (essentially the same as carbon, 2.58); it is difficult to imagine this scenario accounting for all of the observed favorable effects. It is possible that the sulfur lone pairs could interact favorably with the ring hydrogens (35). However this interaction would depend greatly upon the geometry of the bound inhibitor.…”

“…Pi-stacking or sulfuraromatic interactions in general have been shown to occur extensively in proteins between amino acid residues (32-34). However, very few reports have examined these effects in small molecules (35). Interactions of this type in proteins (e.g.…”

“…Consequently, dispersion interactions are more suitable given the highly polarizable nature of both the benzene pi-electron cloud and the sulfur empty d-orbitals (37). However, Zauhar et al (35) report that while sulfur-aromatic energies tend to include a large van der Waals contribution, the electrostatic component is still of significant size, suggesting that sulfur-aromatic interactions may have significant hydrogen bond character. In addition it has been reported (33) that sulfur-aromatic interactions in a β-hairpin, which placed a methionine side chain in close proximity to an aryl side chain, were predominantly due to hydrophobic effects.…”

“…Pi-stacking or sulfuraromatic interactions in general have been shown to occur extensively in proteins between amino acid residues (32-34). However, very few reports have examined these effects in small molecules (35 Determining the exact factors leading to an energetically favorable sulfur-aromatic interaction is not trivial. In this particular case, the lack of a free hydrogen on a thiol (such as that present in cysteine) simplifies the possible interactions because direct hydrogen bonding can be ruled out.…”