Kamil Wojtkowiak

In the article, we present some of the research topics being pursued by the Structure and Dynamics of Macrosystems research group. We try to connect experimental findings with theoretical description providing new knowledge and understanding of processes at molecular level. Using a variety of theoretical methods, we explain and supplement the results of experiments. Crystal engineering is a branch of science developing rapidly over the past few years. Based on this, we can design and control the crystal formation process, and thus obtain a structure with the desired physicochemical properties. Here, we show how crystal engineering has been combined with computational chemistry using as an example three-dimensional (3D) coordination polymer (CP) CuI/CuII of mixed valence {[Cu3(C14H8N3O2)2(H2O)2](BF4)2}n with 2-(pyrazin-2-yl)quinoline-4-carboxylic acid as a linking ligand obtained based on solvothermal synthesis using Berghof reactors. Another interesting issue is an application of molecular dynamics in ab initio and classical schemes to describe molecular features of compounds with hydrogen bond. Usually, we perform simulations in the gas phase, with liquid or in the solid state depending on the project and therefore computational setup. A few years ago, we decided to study dynamical properties of the hydrogen bonds in one of the polymorphic forms of naphthazarin. We combined static quantum-chemistry approaches with Car-Parrinello Molecular Dynamics (CP-MD). The combination of various methods allowed a detailed description of the proton dynamics in the hydrogen bridges. From the beginning, in the research group we perform investigations of biologically relevant compounds/macromolecules. We focused on selected quinolone carboxylic acid derivatives, because of their biological potential and possible practical applications as well as because of the various kinds of the intramolecular hydrogen bond present in the set of the studied compounds. Based on the obtained results, we were able to draw conclusions of the time-evolution of the hydrogen bridges and their influence on the molecular properties. The last topic, which we would like to introduce in the article is an application of the classical molecular dynamics to study extremophilic proteins. The search for examples of differences in the dynamics and structural properties of mesophilic and thermophilic proteins led to molecular dynamics (MD) simulations for a protein fragment from the bacterium Caldanaerobacter subterraneus subsp. tengcongensis (formerly Thermoanaerobacter tengcongensis) with a type 3 fibronectin domain (FN3) structure. Nowadays, the area of research seems to be very interesting and challenging therefore we put an effort to understand and explain some dependencies in such organisms to provide new knowledge useful in the design of new proteins with particular biological preferences.

In this research, a series of novel hydrazone derivatives based on pyrazolopyridothiazinylacetohydrazide were designed, synthesized, and evaluated for their in vitro cytotoxic potency on several human colon cancer cells (HTC116, HT‐29, and LoVo). After MTT and SRB assays four of the most active derivatives: hydrazide GH and hydrazones GH7, GH8, and GH11, were chosen for further investigation. Hydrazone GH11 had the highest cytotoxic activity (IC₅₀ values of c.a. 0.5 μM). Additionally, the impact of novel derivatives on the oxidative stress level, apoptosis induction, and modulation of inflammation in colon cancer cells was examined. In all studies, the activity of the derivatives increased in order GH < GH7 < GH8 < GH11. At the same time, most of the research was conducted on compounds combined with apple pectin (PC). The most interesting observation was that all the studied derivatives applied together with PC showed significantly higher activity than observed in the case of using PC, hydrazide, or hydrazones separately. Finally, computational chemistry methods (molecular modeling and Density Functional Theory – DFT) were used to complement the experimental studies.

Lead halide perovskites are structurally not stable due to their ionic bonds. Using sulfur agents in the crystal growth improves the stability and performance of the photovoltaic and light‐emitting devices. In this theoretical work, we use a small toy S‐radical in place of A cation in the bulk of lead iodide perovskite, and highlight the significance of the Pb−S covalent‐double‐bond formation for: the charge redistribution on the neighboring bonds that also turn to be covalent, phase transformation to a stable non‐perovskite structure, and superior optoelectronic properties. The chemical analysis was performed with the Quantum Theory of Atoms In Molecules (QTAIM) and Non‐Covalent Interactions (NCI) index. Excitonic properties were obtained from the solution of ab initio Bethe–Salpeter equation. Presence of the spin‐orbit coupling triggers an interplay between the Frenkel and charge‐transfer multiexcitons, switching between the photovoltaic and laser applications. Multiexcitons obey the exciton‐fission preconditions.

The set of TX₃-TrX₂ (T = C, Si, Ge; Tr = B, Al, Ga; X = F, Cl, Br) molecules offers a rather unique opportunity to study both σ-hole and π-hole dimerization on the tetrel and triel ends, respectively. According to the molecular electrostatic potential (MEP) distribution, the π-hole extrema (acidic sites) were more intense than their σ-hole counterparts. The molecules owning the most (CX₃-AlX₂) and least (SiX₃-BX₂) intense π-holes were chosen to evaluate their capacities to attract one and two HCN molecules (Lewis bases). We discovered that the energetic characteristics of π-hole dimers severely conflict with the monomers MEP pattern since the weakest π-hole monomer forms a dimer characterized by interaction energy compared to those created by the monomers with noticeably greater power in the π-hole region. This outcome is due to the deformation of the weakest π-hole donor. Furthermore, the MEP analysis for monomers in the geometry of respective dimers revealed a “residual π-hole” site that was able to drive second ligand attachment, giving rise to the two “unusual trimers” examined further by the NCI and QTAIM analyses. Apart from them, the π-hole/π-hole and σ-hole/π-hole trimers have also been obtained throughout this study and described using energetic and geometric parameters. The SAPT approach revealed details of the bonding in one of the “unusual trimers”. Finally, Born-Oppenheimer Molecular Dynamics (BOMD) simulations were carried out to investigate the time evolution of the interatomic distances of the studied complexes as well as their stability.

The hydrogen bonds properties of 2,6-difluorobenzamide, 5-hydroxyquinoline and 4-hydroxybenzoic acid were investigated by Car–Parrinello and path integral molecular dynamics (CPMD and PIMD), respectively. The computations were carried out in vacuo and in the crystalline phase. The studied complexes possess diverse networks of intermolecular hydrogen bonds (N-H…O, O-H…N and O-H…O). The time evolution of hydrogen bridges gave a deeper insight into bonds dynamics, showing that bridged protons are mostly localized on the donor side; however, the proton transfer phenomenon was registered as well. The vibrational features associated with O-H and N-H stretching were analyzed on the basis of the Fourier transform of the atomic velocity autocorrelation function. The spectroscopic effects of hydrogen bond formation were studied. The PIMD revealed quantum effects influencing the hydrogen bridges providing more accurate free energy sampling. It was found that the N…O or O…O interatomic distances decreased (reducing the length of the hydrogen bridge), while the O-H or N-H covalent bond was elongated, which led to the increase in the proton sharing. Furthermore, Quantum Theory of Atoms in Molecules (QTAIM) was used to give insight into electronic structure parameters. Finally, Symmetry-Adapted Perturbation Theory (SAPT) was employed to estimate the energy contributions to the interaction energy of the selected dimers.

It is postulated that the overexpression of Carbonic Anhydrase isozyme IX in some cancers contributes to the acidification of the extracellular matrix. It was proved that this promotes the growth and metastasis of the tumor. These observations have made Carbonic Anhydrase IX an attractive drug target. In the light of the findings and importance of the glycoprotein in the cancer treatment, we have employed quantum–chemical approaches to study non-covalent interactions in the binding pocket. As a ligand, the acetazolamide (AZM) molecule was chosen, being known as a potential inhibitor exhibiting anticancer properties. First-Principles Molecular Dynamics was performed to study the chalcogen and other non-covalent interactions in the AZM ligand and its complexes with amino acids forming the binding site. Based on Density Functional Theory (DFT) and post-Hartree–Fock methods, the metric and electronic structure parameters were described. The Non-Covalent Interaction (NCI) index and Atoms in Molecules (AIM) methods were applied for qualitative/quantitative analyses of the non-covalent interactions. Finally, the AZM–binding pocket interaction energy decomposition was carried out. Chalcogen bonding in the AZM molecule is an important factor stabilizing the preferred conformation. Free energy mapping via metadynamics and Path Integral molecular dynamics confirmed the significance of the chalcogen bond in structuring the conformational flexibility of the systems. The developed models are useful in the design of new inhibitors with desired pharmacological properties.

Cancer is one of the greatest challenges in modern medicine today. Difficult and long-term treatment, the many side effects of the drugs used and the growing resistance to treatment of neoplastic cells necessitate new approaches to therapy. A very promising targeted therapy is based on direct impact only on cancer cells. As a continuation of our research on new biologically active molecules, we report herein the design, synthesis and anticancer evaluation of a new series of N-Mannich-base-type hybrid compounds containing morfoline or different substituted piperazines moieties, a 1,3,4-oxadiazole ring and a 4,6-dimethylpyridine core. All compounds were tested for their potential cytotoxicity against five human cancer cell lines, A375, C32, SNB-19, MCF-7/WT and MCF-7/DX. Two of the active N-Mannich bases (compounds 5 and 6) were further evaluated for growth inhibition effects in melanoma (A375 and C32), and normal (HaCaT) cell lines using clonogenic assay and a population doubling time test. The apoptosis was determined with the neutral version of comet assay. The confocal microscopy method enabled the visualization of F-actin reorganization. The obtained results demonstrated that compounds 5 and 6 have cytotoxic and proapoptotic effects on melanoma cells and are capable of inducing F-actin depolarization in a dose-dependent manner. Moreover, computational chemistry approaches, molecular docking and electrostatic potential were employed to study non-covalent interactions of the investigated compounds with four receptors. It was found that all the examined molecules exhibit a similar binding affinity with respect to the chosen reference drugs.

Oxaliplatin, similar to Cisplatin, exhibits anticancer activity by interacting with DNA and inducing programmed cell death. It is biotransformed through a number of spontaneous and non-enzymatic processes. In this way, several transient reactive species are formed, including dichloro-, monochloro-, and diaqua-DACH platin, which can complex with DNA and other macromolecules. The molecular level suggests that such interactions can also take place with vitamins containing aromatic rings with lone pair orbitals. Theoretical and experimental studies were performed to investigate interactions of vitamins from the B group with Oxaliplatin, and the results were compared with values characterizing native purines. Quantum-chemical simulations were carried out at the B3LYP/6-31G(d,p) level, with the LANL2DZ basis set representing atomic orbitals of platinum atom, and at the MN15/def2-TZVP levels of theory with the use of Polarizable Continuum Model (IEF-PCM formulation) and water as a solvent. Additionally, time-dependent density functional theory (TD-DFT) was employed to study molecular properties in the electronic excited state. Interactions of vitamins and Oxaliplatin were investigated using UV-Vis spectroscopy. Values of the free energy (ΔG_r) indicate spontaneous reactions with monoaqua [PtH₂OClDACH]⁺ and diaqua [Pt(H₂O)₂DACH]²⁺ derivatives of Oxaliplatin. However, diaqua derivatives were found to be preferable. The free energy (ΔG_r) values obtained for vitamins from the B group indicate lower affinity of Oxaliplatin compared with values characterizing complexes formed by guanine, adenine, and cytosine. The exception is the monoaqua form of vitamin B1 (thiamine) at the MN15/def2-TZVP levels of calculations. An application of atoms in molecules (AIM) theory revealed non-covalent interactions present in the complexes studied. The comparison of computed and experimental spectroscopic properties showed a good agreement.