Halogen-Ionic Bridges: Do They Exist in the Biomolecular World?

If considering that the pronouncedly charged halide anions are ubiquitous in the biological world, then it is interesting to ask whether the halogen-ionic bridges-this term is named by us to describe the interaction motif of a nonbonded halogen ion with two or more electrophiles simultaneously-commonly exist in biomolecules and how they contribute to the stability and specificity of biomolecular folding and binding? To address these problems, we herein present a particularly systematic investigation on the geometrical profile and the energy landscape of halogen ions interacting with and bridging between polar and charged molecular moieties in small model systems and real crystal structures, by means of ab initio calculation, database survey, continuum electrostatic analysis, and hybrid quantum mechanics/molecular mechanics examination. All of these unequivocally demonstrate that this putative halide motif is broadly distributed in biomolecular systems (>6000) and can confer a substantial stabilization for the architecture of proteins and their complexes with nucleic acids and small ligands. This stabilization energy is estimated to be generally more than 100 kcal·mol(-1) for gas-phase states or about 20 kcal·mol(-1) for solution conditions, which is much greater than that found in sophisticated water-mediated (<10 kcal·mol(-1)) and salt (∼ 3.66 kcal·mol(-1)) bridges. In this respect, we would expect that the proposed halogen-ionic bridge, which has long been unrecognized in the arena of biological repertoires, could be appreciated in chemistry and biology communities and might be exploited as a new and versatile tool for rational drug design and bioengineering.