Automatic molecular fragmentation by evolutionary optimisation.

Molecular fragmentation is an effective suite of approaches to reduce the formal computational complexity of quantum chemistry calculations while enhancing their algorithmic parallelisability. However, the practical applicability of fragmentation techniques remains hindered by a dearth of automation and effective metrics to assess the quality of a fragmentation scheme. In this article, we present the Quick Fragmentation via Automated Genetic Search (QFRAGS), a novel automated fragmentation algorithm that uses a genetic optimisation procedure to generate molecular fragments that yield low energy errors when adopted in Many Body Expansions (MBEs). Benchmark testing of QFRAGS on protein systems with less than 500 atoms, using two-body (MBE2) and three-body (MBE3) MBE calculations at the HF/6-31G* level, reveals mean absolute energy errors (MAEE) of 20.6 and 2.2 kJ  mol - 1 , respectively. For larger protein systems exceeding 500 atoms, MAEEs are 181.5 kJ  mol - 1 for MBE2 and 24.3 kJ  mol - 1 for MBE3. Furthermore, when compared to three manual fragmentation schemes on a 40-protein dataset, using both MBE and Fragment Molecular Orbital techniques, QFRAGS achieves comparable or often lower MAEEs. When applied to a 10-lipoglycan/glycolipid dataset, MAEs of 7.9 and 0.3 kJ  mol - 1 were observed at the MBE2 and MBE3 levels, respectively.Scientific Contribution This Article presents the Quick Fragmentation via Automated Genetic Search (QFRAGS), an innovative molecular fragmentation algorithm that significantly improves upon existing molecular fragmentation approaches by specifically addressing their lack of automation and effective fragmentation quality metrics. With an evolutionary optimisation strategy, QFRAGS actively pursues high quality fragments, generating fragmentation schemes that exhibit minimal energy errors on systems with hundreds to thousands of atoms. The advent of QFRAGS represents a significant advancement in molecular fragmentation, greatly improving the accessibility and computational feasibility of accurate quantum chemistry calculations.

Energetics and spectroscopic studies of CNO (-) (H 2 O) n $$ {\mathbf{CNO}}

A system associated with several number of weak interactions supports numerous number of stable structures within a narrow range of energy. Often, a deterministic search method fails to locate the global minimum geometry as well as important local minimum isomers for such systems. Therefore, in this work, the stochastic search technique, namely parallel tempering, has been executed on the quantum chemical surface of the CNO (-) (H 2 O) n $$ {\mathrm{CNO}}^{\left(\hbox{-} \right)}{\left({\mathrm{H}}_2\mathrm{O}\right)}_n $$ system for n = 1 $$ n=1 $$ -8 to generate global minimum as well as several number of local minimum isomers. IR spectrum can act as the fingerprint property for such system to be identified. Thus, IR spectroscopic features have also been included in this work. Vertical detachment energy has also been calculated to obtain clear information about number of water molecules in several spheres around the central anion. In addition, in a real experimental scenario, not only the global but also the local minimum isomers play an important role in determining the average value of a particular physically observable property. Therefore, the relative conformational populations have been determined for all the evaluated structures for the temperature range between 20K and 400K. Further to understand the phase change behavior, the configurational heat capacities have also been calculated for different sizes.

Quantum chemical calculations of nitrosamine activation and deactivation pathways for carcinogenicity risk assessment.

N-nitrosamines and nitrosamine drug substance related impurities (NDSRIs) became a critical topic for the development and safety of small molecule medicines following the withdrawal of various pharmaceutical products from the market. To assess the mutagenic and carcinogenic potential of different N-nitrosamines lacking robust carcinogenicity data, several approaches are in use including the published carcinogenic potency categorization approach (CPCA), the Enhanced Ames Test (EAT), in vivo mutagenicity studies as well as read-across to analogue molecules with robust carcinogenicity data. We employ quantum chemical calculations as a pivotal tool providing insights into the likelihood of reactive ion formation and subsequent DNA alkylation for a selection of molecules including e.g., carcinogenic N-nitrosopiperazine (NPZ), N-nitrosopiperidine (NPIP), together with N-nitrosodimethylamine (NDMA) as well as non-carcinogenic N-nitrosomethyl-tert-butylamine (NTBA) and bis (butan-2-yl) (nitros)amine (BBNA). In addition, a series of nitroso-methylaminopyridines is compared side-by-side. We draw comparisons between calculated reaction profiles for structures representing motifs common to NDSRIs and those of confirmed carcinogenic and non-carcinogenic molecules with in vivo data from cancer bioassays. Furthermore, our approach enables insights into reactivity and relative stability of intermediate species that can be formed upon activation of several nitrosamines. Most notably, we reveal consistent differences between the free energy profiles of carcinogenic and non-carcinogenic molecules. For the former, the intermediate diazonium ions mostly react, kinetically controlled, to the more stable DNA adducts and less to the water adducts via transition-states of similar heights. Non-carcinogenic molecules yield stable carbocations as intermediates that, thermodynamically controlled, more likely form the statistically preferred water adducts. In conclusion, our data confirm that quantum chemical calculations can contribute to a weight of evidence approach for the risk assessment of nitrosamines.

Size-Increased All-Phenylene Molecular Spoked Wheels - A Combined Theoretical and Experimental Approach.

A lateral expansion of molecular spoked wheels (MSWs) based on an all-phenylene backbone is described. The MSWs contain a central hub, six spokes and a rim that is formed by a sixfold Yamamoto coupling of the respective non-cyclized dodecabromo precursor yielding MSWs with up to 30 phenylene rings in the perimeter. Attempts to prepare compounds of such size without flexible side groups at the spokes were unsuccessful, most probably due to an aggregation and accompanying oligomerization of the precursors during the cyclization. To overcome these problems, fluorene units are inserted into the spokes. These contain additional alkyl chains and lead to a curvature of the wheels. Quantum chemical calculations on the mechanism of the Yamamoto coupling leads to geometry and strain-related criteria for the successful rim closure to the respective MSW. Subsequently, MSWs are prepared with four and even six phenylene units at each edge of the hexagonal wheels. The resulting MSWs are characterized by spectroscopic methods, and additionally some of them are visualized via scanning tunneling microscopy (STM).

Evaluation of the nitrosamine impurities of ACE inhibitors using computational, in vitro, and in vivo methods demonstrate no genotoxic potential.

Evaluation and mitigation of the potential carcinogenic risks associated with nitrosamines in marketed pharmaceutical products are areas of interest for pharmaceutical companies and health authorities alike. Significant progress has been made to establish acceptable intake (AI) levels for N-nitrosamine drug substance-related impurities (NDSRIs) using SAR, however some compounds require experimental data to support derivation of a recommended AI. Many angiotensin-converting enzyme inhibitors, identified by the suffix "pril," have secondary amines that can potentially react to form nitrosamines. Here we consider a structural assessment and metabolism data, coupled with comprehensive in vitro and in vivo (mouse) genotoxicity testing to evaluate this particular class of nitrosamines. N-nitroso ramipril and N-nitroso quinapril, both of which are predicted to have inhibited nitrosamine bioactivation due to steric hinderance and branching at the α-position were non-genotoxic in the in vivo liver comet assay and non-mutagenic in the in vivo Big Blue® mutation and duplex sequencing assays. Predicted metabolism along with in vitro metabolism data and quantum chemical calculations related to DNA interactions offer a molecular basis for the negative results observed in both in vitro and in vivo testing. These nitrosamines are concluded to be non-mutagenic and non-carcinogenic; therefore, they should be controlled according to ICH Q3B guidance. Furthermore, these results for N-nitroso ramipril and N-nitroso quinapril should be considered when evaluating the appropriate AI and control strategy for other structurally similar "pril" NDSRIs.

Role of interaction mode of phenanthrene derivatives as selective PDE5 inhibitors using molecular dynamics simulations and quantum chemical calculations.

Phosphodiesterase type 5 (PDE5) inhibitors play a crucial role in blocking PDE5 to improve erectile dysfunction (ED). However, most PDE5 drugs revealed side effects including the loss of vision due to the PDE6 inhibition. Phenanthrene derivatives isolated from E. macrobulbon were previously reported as PDE5 inhibitors. Two phenanthrene derivatives (cpds 1-2) revealed better inhibition to PDE5 than PDE6 and cpd 1 is more selective to PDE5 than cpd 2. To elucidate why the phenanthrene derivatives could inhibit PDE5 and PDE6, their binding modes were investigated using molecular dynamics simulations and quantum chemical calculations, as compared to the PDE5 drugs. From the results, all four drugs and phenanthrene derivatives revealed similar π-π interactions to Phe820 in PDE5. Additional H-bond interaction to Gln817 in PDE5 resulted in better PDE5 inhibition of vardenafil and tadalafil. Moreover, cpds 1-2 were able to form the H-bond interaction with Asp764 in PDE5. In the case of the PDE6, the loss of π-π interaction to Phe776 and H-bond interaction to Gln773 indicated the important points for losing the PDE6 inhibition. In conclusion, to develop the new potent PDE5 inhibitors, not only the important interaction with PDE5 but also the interaction with PDE6 should be considered. In phenanthrene derivatives, the middle ring was significant to form π-π interactions to Phe820 in PDE5 and hydroxyl substituent was also the key part to form the H-bond interaction with Asp764 in PDE5. Principal component analysis (PCA) and free energy landscape (FEL) analysis indicated the stability of the system. The bioavailability, drug-likeness, and pharmacokinetics of phenanthrene derivatives were also predicted. These derivatives revealed good drug-likeness and GI absorption. The obtained results showed that phenanthrene derivatives could be interesting for the development of PDE5 inhibitors in the future.

Physical properties and antioxidant activity of curcumin­zinc metal-organic frameworks.

Metal-organic frameworks (MOFs) offer diverse applications in the food industry, facilitating loading, protection, and controlled release of functional ingredients despite encountering loading capacity and functional activity limitations. This study focuses on curcumin­zinc MOFs, harnessing curcumin's renowned health benefits and zinc to enhance pharmacological properties. We evaluated their synthesis efficiency, stability under varying conditions (pH, salt concentration, temperature), loading and antioxidant capacity. The results showed that microwave synthesis yielded MOFs with a 23.2 ± 4.5% yield, stable within pH 4-10, gradually decomposing in PBS. DPPH, ABTS, and H2O2 assays revealed varying free radical scavenging abilities. MOFs disintegrate in either acidic environments or contain H2O2 (at a concentration threshold of 10 µM). Post-disintegration, these MOFs significantly inhibiting the secretion of TNF-α by RAW264.7 cells induced by LPS. These findings highlight the potential of novel curcumin­zinc MOF materials for nutrient delivery, addressing challenges in effectively delivering functional ingredients.

Unveiling the Nature and Strength of Selenium-Centered Chalcogen Bonds in Binary Complexes of SeO2 with Oxygen-/Sulfur-Containing Lewis Bases: Insights from Theoretical Calculations.

Among various non-covalent interactions, selenium-centered chalcogen bonds (SeChBs) have garnered considerable attention in recent years as a result of their important contributions to crystal engineering, organocatalysis, molecular recognition, materials science, and biological systems. Herein, we systematically investigated π-hole-type Se∙∙∙O/S ChBs in the binary complexes of SeO2 with a series of O-/S-containing Lewis bases by means of high-level ab initio computations. The results demonstrate that there exists an attractive interaction between the Se atom of SeO2 and the O/S atom of Lewis bases. The interaction energies computed at the MP2/aug-cc-pVTZ level range from -4.68 kcal/mol to -10.83 kcal/mol for the Se∙∙∙O chalcogen-bonded complexes and vary between -3.53 kcal/mol and -13.77 kcal/mol for the Se∙∙∙S chalcogen-bonded complexes. The Se∙∙∙O/S ChBs exhibit a relatively short binding distance in comparison to the sum of the van der Waals radii of two chalcogen atoms. The Se∙∙∙O/S ChBs in all of the studied complexes show significant strength and a closed-shell nature, with a partially covalent character in most cases. Furthermore, the strength of these Se∙∙∙O/S ChBs generally surpasses that of the C/O-H∙∙∙O hydrogen bonds within the same complex. It should be noted that additional C/O-H∙∙∙O interactions have a large effect on the geometric structures and strength of Se∙∙∙O/S ChBs. Two subunits are connected together mainly via the orbital interaction between the lone pair of O/S atoms in the Lewis bases and the BD*(OSe) anti-bonding orbital of SeO2, except for the SeO2∙∙∙HCSOH complex. The electrostatic component emerges as the largest attractive contributor for stabilizing the examined complexes, with significant contributions from induction and dispersion components as well.

The Perfluoro-o-phenylene-mercury Trimer [Hg(o-C6F4)]3 - a Textbook Example of Phase-Dependent Structural Differences.

The geometric and electronic structure of [Hg(o-C6F4)]3 (1) in the gas phase, i. e. free of intermolecular interactions, was determined by a synchronous gas-phase electron diffraction/mass spectrometry experiment (GED/MS), complemented by quantum chemical calculations. 1 is stable up to 498 K and the gas phase contains a single molecular form: the trimer [Hg(o-C6F4)]3. It has a planar structure of D3h symmetry with a Hg-C distance of 2.075(5) Šand a Hg-Hg distance of 3.614(7) Š(both rh1). Structural differences between the crystalline and gaseous state have been analyzed. Different DFT functional-basis combinations were tested, demonstrating the importance to consider the relativistic effects of the mercury atoms. The combination PBE0/MWB(Hg),cc-pVTZ(C,F) turned out to be the most appropriate for the geometry optimization of such organomercurials. The electronic structure of 1, the nature of the chemical bonding in C-Hg-C fragments and the nature of the Hg⋅⋅⋅Hg interactions have been analyzed in terms of the Natural Bond Orbital (NBO) and Quantum Theory of Atoms in Molecules (QTAIM) approaches. The influence of the nature of halogen substitution on the structure of the molecules in the series [Hg(o-C6H4)]3, [Hg(o-C6F4)]3, [Hg(o-C6Cl4)]3, [Hg(o-C6Br4)]3 was also analyzed.

Pyridyl-Substituted Nitronyl Nitroxides: Comprehensive Magnetochemical and Quantum Chemical Study.

A series of pyridyl-substituted nitronyl nitroxides was synthesized and structurally characterized. A comprehensive magnetochemical and quantum chemical study of extended raw of the nitroxides with different substituents R in the pyridine fragment was performed. It was shown, that temperature-dependent magnetic properties are determined by the short contacts between nitroxide groups of adjacent molecules as well as between nitroxide group and methyl substituents in the pseudo axial positions of imidazoline fragments. Quantum chemistry allows to select the appropriate model of exchange cluster for analysis of experimental magnetic data and evaluation of the exchange interaction parameters. For NN-PyCl the "order-disorder" transition was detected by means of low temperature XRD. The difference in the experimental and calculated exchange interaction energies may serve as an indicator of temperature-induced structural rearrangements. For instance, for methyl substituted nitronyl nitroxide NN-PyMe structural transformations and significant changes in exchange interaction energies were observed.

Synthesis and Characterization of a Copper Dinitrogen Complex Supported by a Weakly Coordinating Anion.

We report the synthesis and full characterization of the copper dinitrogen complex [(η1-N2)Cu{Al(ORF)4}] 2 (RF=C(CF3)3) prepared by a cascade metathesis reaction of Ag[Al(ORF)4] with CuI-excess in iso-perfluorohexane (i-pfh) under N2 atmosphere. Title compound 2 features an extraordinarily high N2 stretching frequency at 2313/2314 cm-1 (IR/Raman) and was characterized by single-crystal and powder X-ray diffractometry. Quantum chemical charge displacement analysis based on natural orbitals of chemical valence (CD-NOCV) indicates that the copper-dinitrogen interaction is still governed by weak π-backdonation, but is significantly reduced compared to all literature-known transition metal dinitrogen complexes.

Alendronate as Bioactive Coating on Titanium Surfaces: An Investigation of CaP-Alendronate Interactions.

The surface modification of dental implants plays an important role in establishing a successful interaction of the implant with the surrounding tissue, as the bioactivity and osseointegration properties are strongly dependent on the physicochemical properties of the implant surface. A surface coating with bioactive molecules that stimulate the formation of a mineral calcium phosphate (CaP) layer has a positive effect on the bone bonding process, as biomineralization is crucial for improving the osseointegration process and rapid bone ingrowth. In this work, the spontaneous deposition of calcium phosphate on the titanium surface covered with chemically stable and covalently bound alendronate molecules was investigated using an integrated experimental and theoretical approach. The initial nucleation of CaP was investigated using quantum chemical calculations at the density functional theory (DFT) level. Negative Gibbs free energies show a spontaneous nucleation of CaP on the biomolecule-covered titanium oxide surface. The deposition of calcium and phosphate ions on the alendronate-modified titanium oxide surface is governed by Ca2+-phosphonate (-PO3H) interactions and supported by hydrogen bonding between the phosphate group of CaP and the amino group of the alendronate molecule. The morphological and structural properties of CaP deposit were investigated using scanning electron microscopy, energy dispersive X-ray spectroscopy, X-ray diffraction and attenuated total reflectance Fourier transform infrared spectroscopy. This integrated experimental-theoretical study highlights the spontaneous formation of CaP on the alendronate-coated titanium surface, confirming the bioactivity ability of the alendronate coating. The results provide valuable guidance for the promising forthcoming advancements in the development of biomaterials and surface modification of dental implants.

Polymer Nanocomposite Based on Pyrolyzed Polyacrylonitrile Doped with Carbon Nanotubes: Synthesis, Properties, and Mechanism of Formation.

The paper investigates the possibility of fabricating a carbon nanotubes (CNT)-modified nanocomposite based on pyrolyzed polyacrylonitrile (PPAN). The layered structure of PPAN ensures the attachment of nanotubes (NT) to the polymer matrix, forming enhanced PPAN/CNT nanocomposites. We synthesized a PPAN/CNT polymer nanocomposite and investigated its mechanical, conductive, and electronic properties. Using the quantum chemical method density functional theory (DFT), we studied an interaction mechanism between PPAN and single-walled carbon nanotubes. We described the structural features and electron energy structure of the obtained systems. We found that the attachment of a CNT to the PPAN matrix increases tensile strength, electrical conductivity, and thermal stability in the complex. The obtained materials were exposed to electromagnetic radiation and the dielectric constant, reflection, transmission, and absorption coefficients were measured. The study demonstrates the possibility of using carbon nanotubes for reinforcing polyacrylonitrile polymer matrix, which can result in the development of an enhanced class of materials possessing the properties of both polymers and CNTs.

Hovendulcisic acid A-D: four novel ceanothane-type triterpenoids from Hovenia dulcis stems with anticancer properties.

Sixteen ceanothane-type triterpenoids, including four new compounds-hovendulcisic acids A-D (1-4) -were purified from the stems of Hovenia dulcis Thunb. The structures of 1-4 were confirmed by comprehensive means including ECD and quantum chemical calculations. Putative biosynthetic pathways of 1-16 were proposed, and 3, 5, and 15 exhibited antitumor activity on A549 and MDA-MB-231 cells.

Copper(II) coordination to the intrinsically disordered region of SARS-CoV-2 Nsp1.

The intrinsically disordered C-terminal peptide region of severe acute respiratory syndrome coronavirus 2 nonstructural protein-1 (Nsp1-CT) inhibits host protein synthesis by blocking messenger RNA (mRNA) access to the 40S ribosome entrance tunnel. Aqueous copper(II) ions bind to the disordered peptide with micromolar affinity, creating a possible strategy to restore protein synthesis during host infection. Electron paramagnetic resonance (EPR) and tryptophan fluorescence measurements on a 10-residue model of the disordered protein region (Nsp1-CT10), combined with advanced quantum mechanics calculations, suggest that the peptide binds to copper(II) as a multidentate ligand. Two optimized computational models of the copper(II)-peptide complexes were derived: One corresponding to pH 6.5 and the other describing the complex at pH 7.5 to 8.5. Simulated EPR spectra based on the calculated model structures are in good agreement with experimental spectra.

Modulating Hydrogen Shuttling in Ammonia by Neutral and Cationic Boron-Containing Frustrated Lewis Pairs (FLPs).

Xanthene-backbone FLPs featuring secondary borane functions -B(ArX)H (where ArX=C6F5 (ArF) or C6Cl5 (ArCl)) have been targeted through reactions of the dihydroboranes Me2S ⋅ BArXH2 with [4,5-xanth(PR2)Li]2 (R=Ph, iPr), and investigated in the synthesis of related cationic systems via hydride abstraction. The reactivity of these systems (both cationic and charge neutral) with ammonia have been probed, with a view to probing the potential for proton shuttling via N-H bond 'activation.' We find that in the case of four-coordinate boron systems (cationic or change neutral), the N-H linkage remains intact, supported by a NH⋅⋅⋅P hydrogen bond which is worth up to 17 kcal mol-1 thermodynamically, and enabled by planarization of the flexible xanthene scaffold. For cationic three coordinate systems, N-to-P proton transfer is viable, driven by the ability of the boron centre to stabilise the [NH2]- conjugate base through N-to-B π bonding. This proton transfer can be shown to be reversible in the presence of excess ammonia, depending on the nature of the B-bound ArX group. It is viable in the case of C6F5 substituents, but is prevented by the more sterically encumbering and secondary donor-stabilising capabilities of the C6Cl5 substituent.

A theoretical study on toluene oxidization by OH radical.

Toluene, a prominent member of volatile organic compounds (VOCs), exerts a substantial adverse influence on both human life and the environment. In the context of advanced oxidation processes, the ·OH radical emerges as a highly efficient oxidant, pivotal in the elimination of VOCs. This study employs computational quantum chemistry methods (G4MP2//B3LYP/6-311++G(d,p)) to systematically investigate the degradation of toluene by ·OH radicals in an implicit solvent model, and validates the rationale of choosing a single-reference method using T1 diagnostics. Our results suggest three possible reaction mechanisms for the oxidation of toluene by ·OH: firstly, the phenyl ring undergoes a hydrogen abstraction reaction followed by direct combination with ·OH to form cresol; secondly, ·OH directly adds to the phenyl ring, leading to ring opening; thirdly, oxidation of sidechain to benzoic acid followed by further addition and ring opening. The last two oxidation pathways involve the ring opening of toluene via the addition of ·OH, significantly facilitating the process. Therefore, both pathways are considered feasible for the degradation of toluene. Subsequently, the UV-H2O2 system was designed to induce the formation of ·OH for toluene degradation and to identify the optimal reaction conditions. It was demonstrated that ·OH and 1O2 are the primary active species for degrading toluene, with their contribution ranking as ·OH > 1O2. The intermediates in the mixture solution after reactions were characterized using GC-MS, demonstrating the validity of theoretical predictions. A comparative study of the toluene consumption rate revealed an experimental comprehensive activation energy of 10.33 kJ/mol, which is consistent with the preliminary activation energies obtained via theoretical analysis of these three mechanisms (0.56 kJ/mol to 13.66 kJ/mol), indicating that this theoretical method can provide a theoretical basis for experimental studies on the oxidation of toluene by ·OH.

A robust computational quest: Discovering potential hits to improve the treatment of pyrazinamide-resistant Mycobacterium tuberculosis.

The rise of pyrazinamide (PZA)-resistant strains of Mycobacterium tuberculosis (MTB) poses a major challenge to conventional tuberculosis (TB) treatments. PZA, a cornerstone of TB therapy, must be activated by the mycobacterial enzyme pyrazinamidase (PZase) to convert its active form, pyrazinoic acid, which targets the ribosomal protein S1. Resistance, often associated with mutations in the RpsA protein, complicates treatment and highlights a critical gap in the understanding of structural dynamics and mechanisms of resistance, particularly in the context of the G97D mutation. This study utilizes a novel integration of computational techniques, including multiscale biomolecular and molecular dynamics simulations, physicochemical and medicinal chemistry predictions, quantum computations and virtual screening from the ZINC and Chembridge databases, to elucidate the resistance mechanism and identify lead compounds that have the potential to improve treatment outcomes for PZA-resistant MTB, namely ZINC15913786, ZINC20735155, Chem10269711, Chem10279789 and Chem10295790. These computational methods offer a cost-effective, rapid alternative to traditional drug trials by bypassing the need for organic subjects while providing highly accurate insight into the binding sites and efficacy of new drug candidates. The need for rapid and appropriate drug development emphasizes the need for robust computational analysis to justify further validation through in vitro and in vivo experiments.

Interplay of halogen bonding and solvation in protein-ligand binding.

Halogen bonding is increasingly utilized in efforts to achieve high affinity and selectivity of molecules designed to bind proteins, making it paramount to understand the relationship between structure, dynamics, and thermodynamic driving forces. We present a detailed analysis addressing this problem using a series of protein-ligand complexes involving single halogen substitutions - F, Cl, Br, and I - and nearly identical structures. Isothermal titration calorimetry reveals an increasingly favorable binding enthalpy from F to I that correlates with the halogen size and σ-hole electropositive character, but is partially counteracted by unfavorable entropy, which is constant from F to Cl and Br, but worse for I. Consequently, the binding free energy is roughly equal for Cl, Br, and I. QM and solvation-free-energy calculations reflect an intricate balance between halogen bonding, hydrogen bonds, and solvation. These advances have the potential to aid future drug design initiatives involving halogenated compounds.