σ-Hole interactions in small-molecule compounds containing divalent sulfur groups R1-S-R2.

Hydrogen bonds, aromatic stacking contacts and σ-hole interactions are all noncovalent interactions commonly observed in biological systems. Structural data derived from the Protein Data Bank showed that methionine residues can interact with oxygen atoms through directional S...O contacts in the protein core. In the present work, the Cambridge Structural Database (CSD) was used in conjunction with ab initio calculations to explore the σ-hole interaction properties of small-molecule compounds containing divalent sulfur. CSD surveys showed that 7095 structures contained R1-S-R2 groups that interact with electronegative atoms like N, O, S and Cl. Frequencies of occurrence and geometries of the interaction were dependent on the nature of R1 and R2, and the hybridization of carbon atoms in C,C-S, and C,S-S fragments. The most common interactions in terms of frequency of occurrence were C,C-S...O, C,C-S...N and C,C-S...S with predominance of Csp2. The strength of the chalcogen interaction increased when enhancing the electron-withdrawing character of the substituents. The most positive electrostatic potentials (VS,max; illustrating positive σ-holes) calculated on R1-S-R2 groups were located on the S atom, in the S-R1 and S-R2 extensions, and increased with electron-withdrawing R1 and R2 substituents like the interaction strength did. As with geometric data derived from the CSD, interaction geometries calculated for some model systems and representative CSD compounds suggested that the interactions were directed in the extensions of S-R1 and S-R2 bonds. The values of complexation energies supported attractive interactions between σ-hole bond donors and acceptors, enhanced by dispersion. The interactions of R1-S-R2 with large VS,max and nucleophiles with large negative VS,min coherently provided more negative energies. According to NBO analysis, chalcogen interactions consisted of charge transfer from a nucleophile lone pair to an S-R1 or S-R2 antibonding orbital. The directional σ-hole interactions at R1-S-R2 can be useful in crystal engineering and the area of supramolecular biochemistry.

Hydrogen bonding at C=Se acceptors in selenoureas, selenoamides and selones.

In recent years there has been considerable interest in chalcogen and hydrogen bonding involving Se atoms, but a general understanding of their nature and behaviour has yet to emerge. In the present work, the hydrogen-bonding ability and nature of Se atoms in selenourea derivatives, selenoamides and selones has been explored using analysis of the Cambridge Structural Database and ab initio calculations. In the CSD there are 70 C=Se structures forming hydrogen bonds, all of them selenourea derivatives or selenoamides. Analysis of intramolecular geometries and ab initio partial charges show that this bonding stems from resonance-induced C(δ+)=Se(δ-) dipoles, much like hydrogen bonding to C=S acceptors. C=Se acceptors are in many respects similar to C=S acceptors, with similar vdW-normalized hydrogen-bond lengths and calculated interaction strengths. The similarity between the C=S and C=Se acceptors for hydrogen bonding should inform and guide the use of C=Se in crystal engineering.

High level QM/MM modeling of the formation of the tetrahedral intermediate in the acylation of wild type and K73A mutant TEM-1 class A beta-lactamase.

The breakdown of beta-lactam antibiotics by beta-lactamases is the most important resistance mechanism of gram negative bacteria against these drugs. The reaction mechanism of class A beta-lactamases, the most widespread family of these enzymes, consists of two main steps: acylation of an active site serine by the antibiotic, followed by deacylation and release of the cleaved compound. We have investigated the first step in acylation (the formation of the tetrahedral intermediate) for the reaction of benzylpenicillin in the TEM-1 enzyme using high level combined quantum mechanics/molecular mechanics (QM/MM) methods. Structures were optimized at the B3LYP/6-31+G(d)/CHARMM27 level, with energies for key points calculated up to the ab initio SCS-MP2/aug-cc-pVTZ/CHARMM27 level. The results support a mechanism in which Glu166 removes a proton (via an intervening water molecule) from Ser70, which in turn attacks the beta-lactam of the antibiotic. Depending on the method used, the calculated barriers range from 3 to 12 kcal mol(-1) for this step, consistent with experimental data. We have also modeled this reaction step in a model of the K73A mutant enzyme. The barrier to reaction in this mutant model is found to be slightly higher: the results indicate that Lys73 stabilizes the transition state, in particular deprotonated Ser70, lowering the barrier by about 1.7 kcal mol(-1). This finding may help to explain the conservation of Lys73, in addition to the role we have previously found for it in the later stages of the reaction (Hermann et al. Org. Biomol. Chem. 2006, 4, 206-210).