Structure–Energy Relationships of Halogen Bonds in Proteins

Abstract

The structures and stabilities of proteins are defined by a series of weak noncovalent electrostatic, van der Waals, and hydrogen bond (HB) interactions. In this study, we have designed and engineered halogen bonds (XBs) site-specifically to study their structure-energy relationship in a model protein, T4 lysozyme. The evidence for XBs is the displacement of the aromatic side chain toward an oxygen acceptor, at distances that are equal to or less than the sums of their respective van der Waals radii, when the hydroxyl substituent of the wild-type tyrosine is replaced by a halogen. In addition, thermal melting studies show that the iodine XB rescues the stabilization energy from an otherwise destabilizing substitution (at an equivalent noninteracting site), indicating that the interaction is also present in solution. Quantum chemical calculations show that the XB complements an HB at this site and that solvent structure must also be considered in trying to design molecular interactions such as XBs into biological systems. A bromine substitution also shows displacement of the side chain, but the distances and geometries do not indicate formation of an XB. Thus, we have dissected the contributions from various noncovalent interactions of halogens introduced into proteins, to drive the application of XBs, particularly in biomolecular design.

Modeling halogen bonding with planewave density functional theory: Accuracy and challenges

“…Halogen bonding (XB) has emerged as an important player in the field of noncovalent interactions, supplementing the ubiquitous hydrogen bonding (HB) in the past decade since its rediscovery. Several attractive physical properties such as the high directionality and tunability of XB strength prompted a plethora of applications in organocatalysis, material science, and drug design . Until now, there has already been several general review papers and books published targeting the chemistry community .…”

Do Halogen–Hydrogen Bond Donor Interactions Dominate the Favorable Contribution of Halogens to Ligand–Protein Binding?

“…3 More recently, a survey of the PDB and QM calculations by Zhu and co-workers detailed the presence of “side-on” C–X···H interactions, though they conclude, “The C–X···H contacts can be, therefore, considered as secondary interaction contributions to C–X···O halogen bonds that play important roles in conferring specificity and affinity for halogenated ligands.” 12 In a subsequent perspective Zhu and co-workers emphasize the importance of C–F···H contributions to ligand–protein interactions while only mentioning, “Furthermore, the mean values of the C–X···H angles for X···H (X = Cl, Br, I) hydrogen bonds are about 100°, whereas the mean C–X···Y angles for halogen bonding interactions in biological system indeed amount to 160° (vide supra).” 13 Similarly, another recent study reported that the introduction of Br and I onto aromatic side chains could lead to the formation of both a halogen bond and an C–X···H interaction; however, the role of the C–X···H interaction was largely ignored in the discussion. 14 Clearly, the presence of perpendicular, side-on, or lateral interactions of halogens with hydrogen bond donors (HBDs) has been noted, but their contribution to ligand–protein affinity appears to be underappreciated. Such lack of appreciation may, in part, be due to the perception that nonlinear (i.e., side-on, lateral, or perpendicular) interactions may not be favorable enough to significantly contribute to ligand–protein binding combined with a lack of a quantitative evaluation of the strength of these interactions using high-level ab initio quantum mechanical calculations.…”

The small molecule GAT1508 activates brain-specific GIRK1/2 channel heteromers and facilitates conditioned fear extinction in rodents

“…In the first 5 ns of this run, a distance around 5Å suggests a direct halogen-hydrogen bond between GAT1508 and T94. In the last 50ns of the MD run, the mean distance between the Br atom of GAT1508 and the OG atom of T94 around 6.39Å suggests that a hydrogen-halogen bond may be stabilized by some other nearby donor residue (73,74). In the GIRK2/2 FD case, this distance stabilized around 12Å during throughout the MD run.…”