Conformational Energy Research Articles

In-silico Homology Modeling and Inhibitors Identification of Breast Cancer

Abstract: Azadirachta Indica (Neem) is the first introduced medicinal plant in ancient medicine system, used for various disease treatments and household remedies. Lots of phytochemicals have been isolated from the various parts of the tree to study their biological activities. Gedunin has shown anticancer activity and act as Heat shock protein 90 (Hsp90) inhibitor. Breast cancer one of the most common cancer which mainly develops from lobules or ducts. Triple-negative Breast Cancer (TNBC) is an aggressive type of breast cancer in which cancer cells does not have hormone receptors. Due to lack of hormone receptors many targeted therapies were developed for advance stage cancer. The interaction between drugs and protein were examined using spectroscopic techniques, to determine the drug stability and binding site of drug in protein. Computer-aided drug design method were used to develop and analyse the drugs. Interaction between protein and drugs visualize by using molecular graphic viewer tools, to identify protein conformation and binding energy of ligand and protein.

Rotational spectrum of anisole-CO2: Cooperative C···O tetrel bond and C[sbnd]H···O hydrogen bond

Rotational spectrum of the 1:1 anisole-CO2 complex has been investigated using a pulsed jet Fourier transform microwave spectrometer supplemented with quantum chemical calculations. In the pulsed jet, only one isomer has been observed which is characterized by a dominant C···O tetrel bond and two CH···OCO2 weak hydrogen bonds. Different theoretical methods predict different orders of relative energies of plausible conformations. The experimental observation is most consistent with the theoretical estimation at the B3LYP-D3(BJ)/6–311++G(d,p) level of theory. Johnson’s non-covalent interaction, quantum theory of atoms in molecules and natural bond orbital analyses have been applied to better understand the nature of non-covalent interactions at play in the anisole-CO2 complex.

Synthesis, In silico Molecular Docking Studies and antimicrobial evaluation of Some New Anthracene Derivatives Tagged with Arylidene, Pyridine, Oxazole, and Chromene Moieties as Promising Inhibitors of Bacterial DNA gyrase

Here, A series of unprecedented derivatives of several heterocyclic compounds, including arylidene, pyridine, oxazole, and chromene, were designed with the anthracene moiety starting from 2-cyano-pyrroloanthracen acetamide (1). The chemical composition of all synthesized compounds was established by spectral analysis FT-IR, 1H-NMR, 13C-NMR, and Mass spectra. Also, the new compounds were docked to the active site of the DNA gyrase B chain enzyme, and the suitable binding interactions were displayed according to their bond lengths and conformational energies. The structure-activity relationship analysis showed that the antimicrobial activity could be modulated by the existence of anthracene moiety, electron-withdrawing groups, and amide linkage. In silico ADMET (absorption, metabolic, distribution, toxicity, and excretion) predictions for the compounds 1-7 were calculated to gain insight into their pharmacokinetics, safety, and drug-likeness profile. The antimicrobial investigations of all synthesized molecules were achieved against Gram-negative (Escherichia coli) and Gram-positive (Bacillus cereus) bacterial strains. Results indicated that the compounds exhibited promising activity against strains. Therefore, the newly hybrid anthracene molecules could serve as promising chemical scaffolds to develop upcoming drug candidates as antimicrobial agents.

Potential topoisomerases inhibitors from Aspergillus terreus using virtual screening

Cancer is appraised as one of the predominant reasons for demise worldwide. Owing to the continued resistance to the anti-topoisomerases, the worldwide challenge is the discovery of new drugs and maintenance their topoisomerase sensitivity. Therefore, the main goal of this work is to assess the potential anti-cancer effect of the ethyl acetate extracts derived from different broth media of the endophytic Aspergillus terreus AArEF2 isolated from Artemisia arboresscens L. versus HepG-2 and MCF-7 cell lines and to estimate the ability of the most potent cytotoxic extract to inhibit topoisomerase I and II enzyme activity. The findings revealed that the ethyl acetate extract afforded from the modified potato dextrose broth (MPDB) media displayed the highest cytotoxic activities with IC50 values of 7.92 and 8.53 µg/mL towards HepG-2 and MCF-7 cell lines, respectively and showed substantial inhibition towards topoisomerase I and II with IC50 values of 8.76 and 2.83 µg/mL, respectively. HPLC-ESI-HRMS analysis of such extract annotated fifteen metabolites belonging to various classes, some of which were reported for their cytotoxic activities. Regarding docking analysis, most compounds showed strong conformational energies higher than positive control drugs, particularly averantin (12) and asterredione (14), which demonstrated promising interaction abilities with Topo I and Topo II binding sites, respectively, emphasizing probable involvement of such compounds to the noteworthy cytotoxic potentials of the ethyl acetate extract of MPDB media. Also, molecular dynamics simulation has been done to confirm the docking results. These findings might point up the probable chemotherapeutic applications of Aspergillus terreus AArEF2 isolated from A. arboresscens.

The Use of Bridging Ligand Substituents to Bias the Population of Localized and Delocalized Mixed-Valence Conformers in Solution.

The electronic structure and associated spectroscopic properties of ligand‐bridged, bimetallic ‘mixed‐valence’ complexes of the general form {M}(μ‐B){M+} are dictated by the electronic couplings, and hence orbital overlaps, between the metal centers mediated by the bridge. In the case of complexes such as [{Cp*(dppe)Ru}(μ‐C≡CC6H4C≡C){Ru(dppe)Cp*}]+, the low barrier to rotation of the half‐sandwich metal fragments and the arylene bridge around the acetylene moieties results in population of many energy minima across the conformational energy landscape. Since orbital overlap is also sensitive to the particular mutual orientations of the metal fragment(s) and arylene bridge through a Karplus‐like relationship, the different members of the population range exemplify electronic structures ranging from strongly localized (weakly coupled Robin‐Day Class II) to completely delocalized (Robin‐Day Class III). Here, we use electronic structure calculations with the hybrid density functional BLYP35‐D3 and a continuum solvent model in combination with UV‐vis‐NIR and IR spectroelectrochemical studies to show that the conformational population in complexes [{Cp*(dppe)Ru}(μ‐C≡CArC≡C){Ru(dppe)Cp*]+, and hence the dominant electronic structure, can be biased through the steric and electronic properties of the diethynylarylene (Ar) moiety (Ar=1,4‐C6H4, 1,4‐C6F4, 1,4‐C6H2‐2,5‐Me2, 1,4‐C6H2‐2,5‐(CF3)2, 1,4‐C6H2‐2,5‐iPr2).

Molecular Dynamics Simulation of a tRNA-Leucine Dimer with an A3243G Heteroplasmy Mutation in Human Mitochondria Using a Secondary Structure Prediction Approach

Mitochondrial DNA mutations, such as A3243G, can affect changes in the structure of biomolecules, resulting in changes in the structure of Leucine transfer Ribose Nucleic Acid to form a dimer. Dimer structure modeling is needed to determine the properties of the structure. However, the lack of a structure template for the transfer of Ribose Nucleic Acid (tRNA) is challenging for the modeling of mutant structures of tRNA, especially mitochondrial tRNA that are susceptible to mutation. Therefore, this study predicted the structure of mitochondrial leucine tRNA and its stability through a knowledge-based method and molecular dynamics. Structural modeling and initial assessment were performed using RNAComposer and MolProbity, HNADOCK, and Discovery studios to form the dimer structure. Molecular dynamics simulations for stability analysis were performed using Amber and AmberTools20 software, showing that the conformational energy of the mutant leucine tRNA dimer structure was lower than the native structure. Moreover, the Root Mean Square Deviation (RMSD) of monomer native leucine tRNA was lower than the mutant, indicating that the dimer structure of mutant leucine tRNA is more stable than usual, and the normal leucine tRNA is more stable than the mutant.

Evaluation of residue variability in a conformation-specific context and during evolutionary sequence reconstruction narrows drug resistance selection in Abl1 tyrosine kinase.

Diseases with readily available therapies may eventually prevail against the specific treatment by the acquisition of resistance. The constitutively active Abl1 tyrosine kinase known to cause chronic myeloid leukemia is an example, where patients may experience relapse after small inhibitor drug treatment. Mutations in the Abl1 tyrosine kinase domain (Abl1‐KD) are a critical source of resistance and their emergence depends on the conformational states that have been observed experimentally: the inactive state, the active state, and the intermediate inactive state that resembles Src kinase. Understanding how resistant positions and amino acid identities are determined by selection pressure during drug treatment is necessary to improve future drug development or treatment decisions. We carry out in silico site‐saturation mutagenesis over the Abl1‐KD structure in a conformational context to evaluate the in situ and conformational stability energy upon mutation. Out of the 11 studied resistant positions, we determined that 7 of the resistant mutations favored the active conformation of Abl1‐KD with respect to the inactive state. When, instead, the sequence optimization was modeled simultaneously at resistant positions, we recovered five known resistant mutations in the active conformation. These results suggested that the Abl1 resistance mechanism targeted substitutions that favored the active conformation. Further sequence variability, explored by ancestral reconstruction in Abl1‐KD, showed that neutral genetic drift, with respect to amino acid variability, was specifically diminished in the resistant positions. Since resistant mutations are susceptible to chance with a certain probability of fixation, combining methodologies outlined here may narrow and limit the available sequence space for resistance to emerge, resulting in more robust therapeutic treatments over time.

Non-Equilibrium Protein Folding and Activation by ATP-Driven Chaperones.

Recent experimental studies suggest that ATP-driven molecular chaperones can stabilize protein substrates in their native structures out of thermal equilibrium. The mechanism of such non-equilibrium protein folding is an open question. Based on available structural and biochemical evidence, I propose here a unifying principle that underlies the conversion of chemical energy from ATP hydrolysis to the conformational free energy associated with protein folding and activation. I demonstrate that non-equilibrium folding requires the chaperones to break at least one of four symmetry conditions. The Hsp70 and Hsp90 chaperones each break a different subset of these symmetries and thus they use different mechanisms for non-equilibrium protein folding. I derive an upper bound on the non-equilibrium elevation of the native concentration, which implies that non-equilibrium folding only occurs in slow-folding proteins that adopt an unstable intermediate conformation in binding to ATP-driven chaperones. Contrary to the long-held view of Anfinsen’s hypothesis that proteins fold to their conformational free energy minima, my results predict that some proteins may fold into thermodynamically unstable native structures with the assistance of ATP-driven chaperones, and that the native structures of some chaperone-dependent proteins may be shaped by their chaperone-mediated folding pathways.

Dissecting Solvent Effects on Hydrogen Bonding

AbstractThe experimental isolation of H‐bond energetics from the typically dominant influence of the solvent remains challenging. Here we use synthetic molecular balances to quantify amine/amide H‐bonds in competitive solvents. Over 200 conformational free energy differences were determined using 24 H‐bonding balances in 9 solvents spanning a wide polarity range. The correlations between experimental interaction energies and gas‐phase computed energies exhibited wild solvent‐dependent variation. However, excellent correlations were found between the same computed energies and the experimental data following empirical dissection of solvent effects using Hunter's α/β solvation model. In addition to facilitating the direct comparison of experimental and computational data, changes in the fitted donor and acceptor constants reveal the energetics of secondary local interactions such as competing H‐bonds.

Dissecting Solvent Effects on Hydrogen Bonding.

The experimental isolation of H‐bond energetics from the typically dominant influence of the solvent remains challenging. Here we use synthetic molecular balances to quantify amine/amide H‐bonds in competitive solvents. Over 200 conformational free energy differences were determined using 24 H‐bonding balances in 9 solvents spanning a wide polarity range. The correlations between experimental interaction energies and gas‐phase computed energies exhibited wild solvent‐dependent variation. However, excellent correlations were found between the same computed energies and the experimental data following empirical dissection of solvent effects using Hunter's α/β solvation model. In addition to facilitating the direct comparison of experimental and computational data, changes in the fitted donor and acceptor constants reveal the energetics of secondary local interactions such as competing H‐bonds.

Conformational Energy Benchmark for Longer n-Alkane Chains.

We present the first benchmark set focusing on the conformational energies of highly flexible, long n-alkane chains, termed ACONFL. Unbranched alkanes are ubiquitous building blocks in nature, so the goal is to be able to calculate their properties most accurately to improve the modeling of, e.g., complex (biological) systems. Very accurate DLPNO-CCSD(T1)/CBS reference values are provided, which allow for a statistical meaningful evaluation of even the best available density functional methods. The performance of established and modern (dispersion corrected) density functionals is comprehensively assessed. The recently introduced r2SCAN-V functional shows excellent performance, similar to efficient composite DFT methods like B97-3c and r2SCAN-3c, which provide an even better cost-accuracy ratio, while almost reaching the accuracy of much more computationally demanding hybrid or double hybrid functionals with large QZ AO basis sets. In addition, we investigated the performance of common wave function methods, where MP2/CBS surprisingly performs worse compared to the simple D4 dispersion corrected Hartree-Fock. Furthermore, we investigate the performance of several semiempirical and force field methods, which are commonly used for the generation of conformational ensembles in multilevel workflows or in large scale molecular dynamics studies. Outstanding performance is obtained by the recently introduced general force field, GFN-FF, while other commonly applied methods like the universal force field yield large errors. We recommend the ACONFL as a helpful benchmark set for parametrization of new semiempirical or force field methods and machine learning potentials as well as a meaningful validation set for newly developed DFT or dispersion methods.

Stimulus responsive luminescence and application of rotor type 1,1′-([2,2′-bithiophene]-3,3′-diyl)bis(ethan-1-one) and 3′-acetyl-[2,2′-bithiophene]-3-carbaldehyde as molecular rotors

Two dithiophene aldehyde/ketone derivatives are designed as luminescence molecular rotors, i.e., 1,1′-([2,2′-bithiophene]-3,3′-diyl)bis(ethan-1-one) (BTBE) and 3′-acetyl-[2,2′-bithiophene]-3-carbaldehyde (BTAC). Their absorption and luminescence properties, as well as the stimulus responsive luminescence characteristics of water spikes are studied in detail. In order to further explore relationship of luminescence and molecular structure, three reference compounds are also synthesized, named 1-(2-methylthiophen-3-yl)ethanone (MTE), 2-methylthiophene-3-carbaldehyde (MTC) and 4H-cyclohepta[1,2-b:7,6-b’]dithiophen-4-one (CDTO). BTBE and BTAC have two obvious absorption bands in the short wavelength region with peak wavelengths of about 212 nm and 260 nm, respectively, while there is a weak trailing type absorption band in the range of about 300–400 nm. Their fluorescence spectra show two luminescence bands in the range of 280–350 nm and 400–600 nm, respectively, and the latter is stronger. Compared with the absorption and luminescence spectra of the reference compounds, it is determined that two absorption bands of BTBE and BTAC in shorter wavelength region are derived from the single thiophene ring carbonyl planar unit, while the absorption band in longer region are derived from the integrated structure of dithiophene carbonyl. The fluorescence bands with peaks of about 300 nm and 470 nm originate respectively from the localized F-C vertical excited states (LE), i.e., the excited state from single planar thienyl-carbonyl unit, and integrated excited state (IE), i.e., the excited state from integrated di-thienyl-carbonyl rings linked covalently with less dihedral angle and greater degree of conjugation at excited state. The crystal structure data show that two thiophene rings possess larger dihedral angles in crystal states, 86.9° for BTBE and 60.8° for BTAC, respectively. However, theoretical calculation results prove the conformational stabilization energy changes little, less than 1.5 kcal/mol, as dihedral angle changes from 50° to 100°. Hydrogen bonding is sufficient to overcome the energy required for this conformational change. Therefore, both BTBE and BTAC can produce water stimulation response luminescence behavior. This stimulating response behavior of BTBE and BTAC can be applied to the preparation of water writable film materials.

Randomizing of Oligopeptide Conformations by Nearest Neighbor Interactions between Amino Acid Residues.

Flory’s random coil model assumes that conformational fluctuations of amino acid residues in unfolded poly(oligo)peptides and proteins are uncorrelated (isolated pair hypothesis, IPH). This implies that conformational energies, entropies and solvation free energies are all additive. Nearly 25 years ago, analyses of coil libraries cast some doubt on this notion, in that they revealed that aromatic, but also β-branched side chains, could change the 3J(HNHCα) coupling of their neighbors. Since then, multiple bioinformatical, computational and experimental studies have revealed that conformational propensities of amino acids in unfolded peptides and proteins depend on their nearest neighbors. We used recently reported and newly obtained Ramachandran plots of tetra- and pentapeptides with non-terminal homo- and heterosequences of amino acid residues to quantitatively determine nearest neighbor coupling between them with a Ising type model. Results reveal that, depending on the choice of amino acid residue pairs, nearest neighbor interactions either stabilize or destabilize pairs of polyproline II and β-strand conformations. This leads to a redistribution of population between these conformations and a reduction in conformational entropy. Interactions between residues in polyproline II and turn(helix)-forming conformations seem to be cooperative in most cases, but the respective interaction parameters are subject to large statistical errors.

Nitration of Flavonoids and Tocopherols as Potential Modulators of Nitrosative Stress—A Study Based on Their Conformational Structures and Energy Content

Vitamin E and dietary flavonoids are natural substances with antioxidant and anti-inflammatory activities, showing little or no side effects. Fruit and vegetable diets based on flavonoids and vitamin E provide a benefit to hypertensive subjects by regulating blood pressure. However, the exact mechanism of their anti-inflammatory properties has not been chemically explained. It has been proposed that their anti-oxidant and anti-inflammatory properties may be related to their ability to scavenge free radicals. We here describe the chemical considerations that flavonoids and tocopherols required to act as potential scavengers of the •NO2 radical, a key radical in the cellular oxidative process. Moreover, we provide a theoretical study of the energy content of the nitrated compounds in the different possible positions. With this analysis, it was predicted that five flavonoids from different families (quercetin (flavanol), naringenin (flavanone), luteolin (flavone), catechin (flavanol) and aurantinidin (anthocyanin)) and three tocopherols (β-, γ-, and δ-tocopherol, but not α-tocopherol) could act as potential scavengers of the harmful •NO2 radical. These results may help to explain their beneficial effect on cardiovascular health through its antioxidant role. To validate our theoretical considerations, we also examined uric acid, a well-known •NO2-scavenger. We hope this study could help to elucidate the potential scavenging activity of other dietary antioxidants.

Metadynamics simulations on the key factors of handedness induction of quinoline oligoamide foldamers with a terminal chiral group

AbstractMetadynamics simulation has been used to determine the conformational energy landscapes of several helical quinoline oligoamides bearing β‐pinene‐derived pyridine at either the C or N‐terminus. Based on the experimental results, the helix‐sense preference for four types of foldamers with the chiral terminal group has been verified. To compare to the key factors inducing handedness to helix‐sense preference, a terminal group with three hydrogen bond sites is designed and corresponding foldamers are built. The calculated results show that the delocalization effect and steric hindrance are mainly responsible for a particular helix‐sense preference for the investigated foldamers. The more hydrogen bonds between the terminal group and oligoamide units are formed, the more stable foldamers are.

The role of substrate deformation in context‐dependent non‐CG DNA methylation

Cytosine‐5 DNA methylation is a major epigenetic mechanism that is important for gene regulation and genome stability. Across evolution, the DNA methylation pathways have diversified between different kingdoms. For instance, DNA methylation in mammals predominantly occurs in the context of CG dinucleotides, established by de novo DNA methyltransferases DNMT3A and DNMT3B and maintained by DNMT1. In contrast, DNA methylation in plants occurs in all three sequence contexts in plants, namely CG, CHG and CHH (H = A, C, or T), with CHG and CHH methylation maintained by CHROMOMETHYLASES (CMTs) and Domains Rearranged Methyltransferase 2 (DRM2). Emerging evidence reveals high context‐dependence of non‐CG methylation in plants: both CHG and CHH methylation is enriched with an A or T nucleotide at the +1‐flanking site, providing a mechanism in reinforcing DNA methylation at specific chromatin domains, such as AT‐rich TEs. To understand the context‐dependency of plant non‐CG methylation, we recently characterized the structural basis for the DRM2‐ and CMT3‐mediated non‐CG methylation. Remarkably, DRM2‐ and CMT‐mediated DNA methylation both involve intercalation‐induced base distortion at the +1 target‐flanking site. The conformational energy penalty associated with this DNA deformation is mostly stabilized by van der Waals contacts, rather than base‐specific hydrogen‐bonding interactions that were previously observed for mammalian DNMTs, allowing the potential influence of nucleotide composition at the +1 site on DRM2‐ and CMT‐mediated methylation. These findings establish a link between DNA deformation and context‐dependent non‐CG DNA methylation in plants, providing a new paradigm for the evolutionarily diversified DNA methylation mechanisms.

Extent of Internal Hydration influence the Activation of GPCR Rhodopsin

Rhodopsin is an archetypical GPCR responsible for dim‐light vision, which adopts a dynamic equilibrium between two metastable intermediates, metarhodopsin‐I (MI) and metarhodopsin‐II (MII), upon absorption of light. MI is an inactive conformational state of this GPCR, while MII is a fully active conformational state. We hypothesized that the MI to MII transition following isomerization of the retinal ligand involves a flood of bulk water into the protein core. To observe this change in the hydration level of the receptor during activation that is typically invisible to structural techniques such as X‐ray crystallography or cryo‐EM, we carried out a set of experiments using an osmotic stress approach. In this approach, the hydration level of rhodopsin was changed by placing the protein in native disk membranes in solutions with varying levels of osmotic pressure. Inert hydrophilic polyethylene glycol (PEG) solutes with different molecular weights and concentrations were used as the osmolytes. The effect of osmotic pressure on conformational dynamics was then quantified by measuring the reversible shifting of the metarhodopsin equilibrium using UV‐Visible spectroscopy. Results from these experiments show an influx of 80–100 water molecules into the rhodopsin interior, forming a partially disordered, solvent‐swollen active MII conformational state during photoactivation, a result supported by atomistic molecular dynamics simulations work [1, 2]. Additionally, we observed that the size of the polymer osmolyte played an important role in the modulation of rhodopsin’s activation: large osmolytes (PEG > 600) back shift the equilibrium to inactive MI state, while small osmolytes (PEG < 600) forward‐shift the equilibrium to MII state. We attribute this size dependence to the degree of osmolyte penetration into the rhodopsin core. Large polymers behave similarly to ideal osmolytes and dehydrate rhodopsin, while smaller polymers wriggle into the rhodopsin interior and stabilize the open MII conformation. These results necessitate a new understanding of GPCR activation in which the hydration level of protein is paramount in governing conformational energy landscapes. [1] U. Chawla et al. (2021) Angew. Chem. Int. Ed. 60, 2288–2295. [2] N. Leioatts et al. (2014) Biochemistry 53, 376−385.

Application of Coarse-Grained (CG) Models to Explore Conformational Pathway of Large-Scale Protein Machines.

Protein machines are clusters of protein assemblies that function in order to control the transfer of matter and energy in cells. For a specific protein machine, its working mechanisms are not only determined by the static crystal structures, but also related to the conformational transition dynamics and the corresponding energy profiles. With the rapid development of crystallographic techniques, the spatial scale of resolved structures is reaching up to thousands of residues, and the concomitant conformational changes become more and more complicated, posing a great challenge for computational biology research. Previously, a coarse-grained (CG) model aiming at conformational free energy evaluation was developed and showed excellent ability to reproduce the energy profiles by accurate electrostatic interaction calculations. In this study, we extended the application of the CG model to a series of large-scale protein machine systems. The spike protein trimer of SARS-CoV-2, ATP citrate lyase (ACLY) tetramer, and P4-ATPases systems were carefully studied and discussed as examples. It is indicated that the CG model is effective to depict the energy profiles of the conformational pathway between two endpoint structures, especially for large-scale systems. Both the energy change and energy barrier between endpoint structures provide reasonable mechanism explanations for the associated biological processes, including the opening of receptor binding domain (RBD) of spike protein, the phospholipid transportation of P4-ATPase, and the loop translocation of ACLY. Taken together, the CG model provides a suitable alternative in mechanistic studies related to conformational change in large-scale protein machines.

Comparing the Performances of Force Fields in Conformational Searching of Hydrogen-Bond-Donating Catalysts.

Here, we compare the relative performances of different force fields for conformational searching of hydrogen-bond-donating catalyst-like molecules. We assess the force fields by their predictions of conformer energies, geometries, low-energy, nonredundant conformers, and the maximum numbers of possible conformers. Overall, MM3, MMFFs, and OPLS3e had consistently strong performances and are recommended for conformationally searching molecules structurally similar to those in this study.

Computational study of ground-state properties of μ2 -bridged group 14 porphyrinic sandwich complexes.

The structural properties of μ2 -bridged porphyrinic double-decker complexes are investigated and the influence of various ligands, metals, substituents, and bridging atoms on the dominant structural motif is elucidated. A variety of quantum chemical methods including semiempirical (SQM) methods and density functional theory (DFT) is assessed for the calculation of ecliptic and staggered conformational energies. Local coupled cluster (DLPNO-CCSD(T1)) data are generated for reference. The r2 SCAN-3c composite scheme as well as the B2PLYP-D4/def2-QZVPP approach are identified as reliable methods. Energy decomposition analyses (EDA) and localized molecular orbital analyses (LMO) are used to investigate the bonding situation and the nature of the inter-ligand interaction energy underlining the crucial role of attractive London dispersion interactions. Targeted modification of the bridging atom, e.g., by replacing O2- by S2- is shown to drastically change the major structural features of the investigated complexes. Further, the influence of different substituents of varying size at the phthalocyanine ligand regarding the dominant conformation is described.