Tackling Halogenated Species with PBSA: Effect of Emulating the σ-Hole

Abstract

<div>To model halogen bond phenomena using classical force fields, an extra-point (EP) of charge is frequently introduced at a given distance from the halogen (X) to emulate the σ-hole. The resulting molecular dynamics (MD) trajectories can be used in subsequent molecular mechanics (MM) combined with Poisson–Boltzmann and surface area calculations (MM PBSA) to estimate protein–ligand binding free energies (∆G<sub>bind</sub>). While EP addition improves the MM/MD description of halogen-containing systems, its effect on the calculation of solvation free energies (∆G<sub>solv</sub>) using the PBSA approach is yet to be assessed. As the PBSA calculations depend, among other parameters, on the empirical assignment of radii (PB radii), a problematic issue arises since standard halogen radii are smaller than the typical X· · · EP distances (usually corresponding to R<sub>min</sub>), thus placing the EP within the solvent dielectric. Herein, we performed a comprehensive study on the performance of PBSA (using three different setups) in the calculation of ∆Gsolv values for 142 halogenated compounds (bearing Cl, Br, or I) for which the experimental values are known. By conducting an optimization (minimizing the error against experimental values), we provide a new optimized set of halogen PB radii, for each PBSA setup, that should be used when the EP is located at R min in the context of GAFF. A simultaneous optimization of PB radii and X· · · EP distances shows that a wide range of distance/radius pairs can be used without significant loss of accuracy, therefore laying the basis for expanding this halogen radii optimization strategy to other force fields and EP implementations. As ligand ∆G<sub>solv</sub> estimation is an important term in the determination of protein–ligand ∆G<sub>bind</sub> , this work is particularly relevant in the framework of structure-based virtual screening and related computer-aided drug design routines.</div>

Halogen bond in separation science: A critical analysis across experimental and theoretical results

“…Finally, it is worth mentioning that also for the study of XB in HPLC environment molecular dynamics simulations [22,62] are extremely versatile to reproduce the experimental chromatographic system accounting for solvent effect and mutual conformational adjustment of analyte and selector, and to predict EEO. In particular, good agreement between experimental and simulated data was achieved by using the explicit -hole (ESH) tool [20,21] in order to account for the electrophilic character of the halogen moieties.…”

“…First, halogen substituents can contribute to separation and molecular recognition process by playing multiple roles (hydrophobic site, electron-withdrawing atom, repulsive interaction site, HB acceptor), and the presence of electrophilic regions on bound halogens has to be confirmed theoretically. Indeed, XB comprehension mostly depends on its physical description at theoretical level [20][21][22]. Then, often separation processes occur in solution, and the study of XB in solution [23] is a more demanding task 4 compared to solid state studies.…”

Halogen Bonding: An Underestimated Player in Membrane–drug Interactions

“…d X−EP = R min ) and atomic partial charges are subsequently derived for all atoms by a restrained electrostatic potential (RESP) 82 fitting procedure, although other authors have proposed alternative EP parametrization schemes in the same context. [83][84][85][86][87] The EP approach is easily ported to other force fields, 38 namely OPLS, 88-90 CHARMM 91 or GROMOS, 69 and is compatible with Poisson-Boltzmann and surface area (PBSA) 92,93 or generalized Born (GBSA) 94,95 calculations for estimating protein-ligand binding free energy or hydration free energies. Notice that, despite other less standard approaches being available, 38,96 including force fields specifically designed for biological applications, 97,98 based on QM data, 99 or featuring explicit terms to account for polarization effects, 100-102 these however are not easily generalized for standard force fields.…”

“…Accordingly, the molecular electrostatic potential (ESP) at the HF/6-31G(d) 103-105 level of theory (6-311G(d) 106 basis set in the case of iodine) was generated for the three iodinated molecules, previously optimized at the B3LYP/6-311G(d,p) level of theory, using Gaussian 09. 107 The atomic radius of iodine was set to 2.3Å, 108 similarly to previous work, 69,93 while default Merz-Singh-Kollman (MK) radii were employed for the remaining elements.…”

“…An EP was then introduced along the C-I covalent bond axis, with the C-I-EP angle fixed at 180.0 • and a I-EP distance of 2.15Å, which corresponds to the R min value for iodine in current versions of GAFF, as previously noted. 38,93 Atomic partial charges were subsequently derived by RESP, which was carried out using the antechamber 109 module as implemented in AmberTools 15, 110 thus generating models ibz EP , 5f ibz EP , and iphen EP . Probe topologies were generated by assigning GAFF atom types with the leap tool (Ambertools 15), and converted into GROMACS-compatible format using the acpype 111 tool.…”