Enthalpy–Entropy Compensation in Biomolecular Halogen Bonds Measured in DNA Junctions

Abstract

Interest in noncovalent interactions involving halogens, particularly halogen bonds (X-bonds), has grown dramatically in the past decade, propelled by the use of X-bonding in molecular engineering and drug design. However, it is clear that a complete analysis of the structure-energy relationship must be established in biological systems to fully exploit X-bonds for biomolecular engineering. We present here the first comprehensive experimental study to correlate geometries with their stabilizing potentials for fluorine (F), chlorine (Cl), bromine (Br), or iodine (I) X-bonds in a biological context. For these studies, we determine the single-crystal structures of DNA Holliday junctions containing halogenated uracil bases that compete X-bonds against classic hydrogen bonds (H-bonds), estimate the enthalpic energies of the competing interactions in the crystal system through crystallographic titrations, and compare the enthalpic and entropic energies of bromine and iodine X-bonds in solution by differential scanning calorimetry. The culmination of these studies demonstrates that enthalpic stabilization of X-bonds increases with increasing polarizability from F to Cl to Br to I, which is consistent with the σ-hole theory of X-bonding. Furthermore, an increase in the X-bonding potential is seen to direct the interaction toward a more ideal geometry. However, the entropic contributions to the total free energies must also be considered to determine how each halogen potentially contributes to the overall stability of the interaction. We find that bromine has the optimal balance between enthalpic and entropic energy components, resulting in the lowest free energy for X-bonding in this DNA system. The X-bond formed by iodine is more enthalpically stable, but this comes with an entropic cost, which we attribute to crowding effects. Thus, the overall free energy of an X-bonding interaction balances the stabilizing electrostatic effects of the σ-hole against the competing effects on the local structural dynamics of the system.

Insights into halogen bond-driven enantioseparations

“…This desolvation process was endothermic, so the absolute H values for the second eluted enantiomer of HBipy 29 was lower than that for the first eluted enantiomer. Moreover, if we compare the enthalpy/entropy contributions to retention of 29 to those of the other extreme of the series, namely HBipy 5, we observe that despite both compounds contain iodine and bromine as substituents, in the first case the hindrance generated by the presence of four iodine atoms in close proximity increases the interaction with the CSP and reduces the rotational degree of freedom of the compound ((M)- In this regard, it is interesting to note that, as pointed out by Carter and co-workers [56], despite halogen bonds involving iodine atoms are enthalpically favoured over those involving smaller halogen atoms, this situation may be more than compensated by an entropic penalty due to a crowding effect, resulting in optimal stabilization by a Br· · ·O instead of an I· · ·O interaction. Moreover, it is reported that, in the gas phase, '-hole' interactions with neutral bases are often thermodynamically unfavourable due to the relatively large entropy loss upon complex formation [2].…”

Force Field Model of Periodic Trends in Biomolecular Halogen Bonds

“…Using this system, we have shown that the strength of halogen bonds increases according to the series F < Cl < Br < I, with energies ranging from −0.52 to −6 kcal/mol 17 . In addition, as the X-bonding energy becomes more negative and stabilizing, the geometry becomes more ideal (the Σ R vdW becomes shorter relative to the standard atomic radii and the approach of the acceptor, Θ 1 , becomes more linear towards the σ-hole) 17 .…”

“…The system competes a BXB against analogous H-bonds to stabilize a four-stranded DNA junction 15 and, with the energy of the H-bond now determined, the actual energy of each BXB geometry can be determined in isolation 17, 40 . Using this system, we have shown that the strength of halogen bonds increases according to the series F < Cl < Br < I, with energies ranging from −0.52 to −6 kcal/mol 17 .…”

Molecular dynamics simulation of halogen bonding mimics experimental data for cathepsin L inhibition

“…Our models also explain the favorable effect of a meta-fluorine atom on the binding affinity of ligands with more polarizable iodine atoms interacting with this site, and suggest the existence of an additional secondary halogen bond in the S2 site. As pointed out by Carter et al [37], although halogen bonds involving iodine are enthalpically favored over those involving smaller halogen atoms, this situation may be more than compensated by an entropic penalty due to crowding effects in their DNA model, resulting in optimal stabilization by a BrÁÁÁO instead of an IÁÁÁO interaction. This does not seem to be our case where iodine, as shown experimentally [12], leads to the highest enzyme inhibitory potencies and, in the present study, to the (relatively) shortest XÁÁÁO distances and most favorable C-XÁÁÁO and XÁÁÁO=C angles.…”