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The hydrogen bond acceptor capability of halogens has long been underappreciated in the field of biology. In this work, we have surveyed structures of protein complexes with halogenated ligands to characterize geometrical preferences of C−X···H contacts and contributions of such interactions to protein−ligand binding affinity. Notably, F···H interactions in biomolecules exhibit a remarkably different behavior as compared to three other kinds of X···H (X = Cl, Br, I) interactions, which has been rationalized by means of ab initio calculations using simple model systems. The C−X···H contacts in biological systems are characterized as weak hydrogen bonding interactions. Furthermore, the electrophile “head on” and nucleophile “side on” interactions of halogens have been extensively investigated through the examination of interactions in protein structures and a two-layer ONIOM-based QM/MM method. In biomolecular systems, C−X···H contacts are recognized as secondary interaction contributions to C−X···O halogen bonds that play important roles in conferring specificity and affinity for halogenated ligands. The results presented here are within the context of their potential applications in drug design, including relevance to the development of accurate force fields for halogens. [ABSTRACT FROM AUTHOR]

The blue-shifted C−D stretching vibrations (νCD) of deuteriated dimethyl sulfoxide (DMSO-d6) in mixtures of DMSO-d6/ionic liquid 1-butyl-3-methylimidazolium tetrafluoroborate ([Bmim][BF4]) were carefully investigated and compared with those in DMSO-d6/water. Results from FTIR studies indicate that the direct interaction of C−D···F between DMSO-d6and the anion [BF4−] plays a minor role in the blue-shift of νCDin the mixtures of DMSO-d6/IL. They also show that the indirect influence of the hydrogen bond formed by the nearby functional group SO with C2−H of the cation significantly contributes to the blue-shift of νCD, as can be inferred from the significant differences of the blue-shift in [Bmim][BF4] and 1-butyl-2,3-dimethylimidazolium tetrafluoroborate ([Bm2im][BF4]). In contrast, in the case of DMSO-d6/water mixtures, direct hydration of C−H···O between the methyl groups of DMSO-d6with the oxygen atom of water is mainly responsible for the blue shift of νCD. Furthermore, theoretical calculations revealed that charge migrations as well as rehybridization have a dominant effect on the blue-shift in both mixtures. [ABSTRACT FROM AUTHOR]

AmtB is one of the ammonium transporter proteins facilitating the ammonium transport across the cellular membranes. Experimentally, the substrate used in in vitro studies is the radio labeled [14C]methylammonium, rather than ammonium itself. To explore the similarity and difference of the conduction mechanism of methylamine and ammonia molecules through AmtB, molecular dynamics simulations on 22 carefully designed systems were performed, which demonstrated that methylamine could be automatically transported in a very similar way to ammonia. The driving force for the conduction is mainly the hydrogen bond network comprising His168, His318, and Tyr32, working in coordination with NH−π interaction with residue Trp212. Then, Ser263 translocated the substrates from the exit gate into the cytoplasm by hydrogen bond interaction. The aromatic ring of Trp212 acted like a springboard to facilitate the translocation of the substrates from site Am2 to Am4 via NH−π interaction. Without the mediation of Trp212, further movement of substrate in the channel would be hampered by the strong hydrogen bonding from His168. In agreement with experimental results, the substrates could be transported by W212F mutant but not by W212A within the simulation time as long as 20 ns. In addition, we predicted that the mutants S263D and S263C remain the function of the transporter but S263A does not. The difference of transporting the two substrates is that methylamine involves more hydrophobic interactions than ammonia. In conclusion, methylamine molecule is a good mimic for investigating the translocation mechanism of ammonium transporter AmtB. [ABSTRACT FROM AUTHOR]