Harnessing ChatGPT for Thematic Analysis: Are We Ready?

ChatGPT (OpenAI) is an advanced natural language processing tool with growing applications across various disciplines in medical research. Thematic analysis, a qualitative research method to identify and interpret patterns in data, is one application that stands to benefit from this technology. This viewpoint explores the use of ChatGPT in three core phases of thematic analysis within a medical context: (1) direct coding of transcripts, (2) generating themes from a predefined list of codes, and (3) preprocessing quotes for manuscript inclusion. Additionally, we explore the potential of ChatGPT to generate interview transcripts, which may be used for training purposes. We assess the strengths and limitations of using ChatGPT in these roles, highlighting areas where human intervention remains necessary. Overall, we argue that ChatGPT can function as a valuable tool during analysis, enhancing the efficiency of the thematic analysis and offering additional insights into the qualitative data. While ChatGPT may not adequately capture the full context of each participant, it can serve as an additional member of the analysis team, contributing to researcher triangulation through knowledge building and sensemaking.

σ-Electrons Responsible for Cooperativity and Ring Equalization in Hydrogen-Bonded Supramolecular Polymers.

Invited for this month's cover are collaborators from the TheoCheM group of the Vrije Universiteit Amsterdam and the University of Perugia. The cover picture shows a σ-electron traveling through a hydrogen-bonded squaramide linear chain. The charge transfer within the σ-electronic system is the cause for the cooperativity in the investigated urea, deltamide, and squaramide polymers. More information can be found in the Full Paper by Célia Fonseca Guerra, and co-workers.

How Divalent Cations Interact with the Internal Channel Site of Guanine Quadruplexes.

The front cover artwork is provided by the TheoCheM group of the Vrije Universiteit Amsterdam. The image shows that guanine quadruplexes have a stronger binding affinity for divalent cations than monovalent cations. Read the full text of the Article at 10.1002/cphc.202100529.

σ-Electrons Responsible for Cooperativity and Ring Equalization in Hydrogen-Bonded Supramolecular Polymers.

We have quantum chemically analyzed the cooperative effects and structural deformations of hydrogen-bonded urea, deltamide, and squaramide linear chains using dispersion-corrected density functional theory at BLYP-D3(BJ)/TZ2P level of theory. Our purpose is twofold: (i) reveal the bonding mechanism of the studied systems that lead to their self-assembly in linear chains; and (ii) rationalize the C-C bond equalization in the ring moieties of deltamide and squaramide upon polymerization. Our energy decomposition and Kohn-Sham molecular orbital analyses reveal cooperativity in all studied systems, stemming from the charge separation within the σ-electronic system by charge transfer from the carbonyl oxygen lone pair donor orbital of one monomer towards the σ* N-H antibonding acceptor orbital of the neighboring monomer. This key orbital interaction causes the C=O bonds to elongate, which, in turn, results in the contraction of the adjacent C-C single bonds that, ultimately, makes the ring moieties of deltamide and squaramide to become more regular. Notably, the π-electron delocalization plays a much smaller role in the total interaction between the monomers in the chain.

How Divalent Cations Interact with the Internal Channel Site of Guanine Quadruplexes.

The formation of guanine quadruplexes (GQ) in DNA is crucial in telomere homeostasis and regulation of gene expression. Pollution metals can interfere with these DNA superstructures upon coordination. In this work, we study the affinity of the internal GQ channel site towards alkaline earth metal (Mg2+ , Ca2+ , Sr2+ , and Ba2+ ), and (post-)transition metal (Zn2+ , Cd2+ , Hg2+ , and Pb2+ ) cations using density functional theory computations. We find that divalent cations generally bind to the GQ cavity with a higher affinity than conventional monovalent cations (e. g. K+ ). Importantly, we establish the nature of the cation-GQ interaction and highlight the relationship between ionic and nuclear charge, and the electrostatic and covalent interactions. The covalent interaction strength plays an important role in the cation affinity and can be traced back to the relative stabilization of cations' unoccupied atomic orbitals. Overall, our findings contribute to a deeper understanding of how pollution metals could induce genomic instability.

A Quantitative Molecular Orbital Perspective of the Chalcogen Bond.

Invited for this month's cover are the groups of Prof. Dr. Teodorico C. Ramalho (Federal University of Lavras and University Hradec Kralove) and Prof. Dr. F. Matthias Bickelhaupt (Vrije Universiteit Amsterdam and Radboud University). The cover picture shows the key message of their work, that is, the covalency of the chalcogen bonds, in an elegantly simple and attractive manner. To that end, the chalcogen bonds are represented by schematic 3D structures of the bond donor D2 Ch and the bond acceptor A- , and their attractive interaction in green. Then, a colorful molecular orbital (MO) diagram where the HOMO-LUMO mixing is represented by the mixing of red (HOMO) and blue (LUMO) into purple (MO) is presented. Read the full text of their Full Paper at 10.1002/open.202000323.

A Quantitative Molecular Orbital Perspective of the Chalcogen Bond.

We have quantum chemically analyzed the structure and stability of archetypal chalcogen-bonded model complexes D2 Ch⋅⋅⋅A- (Ch = O, S, Se, Te; D, A = F, Cl, Br) using relativistic density functional theory at ZORA-M06/QZ4P. Our purpose is twofold: (i) to compute accurate trends in chalcogen-bond strength based on a set of consistent data; and (ii) to rationalize these trends in terms of detailed analyses of the bonding mechanism based on quantitative Kohn-Sham molecular orbital (KS-MO) theory in combination with a canonical energy decomposition analysis (EDA). At odds with the commonly accepted view of chalcogen bonding as a predominantly electrostatic phenomenon, we find that chalcogen bonds, just as hydrogen and halogen bonds, have a significant covalent character stemming from strong HOMO-LUMO interactions. Besides providing significantly to the bond strength, these orbital interactions are also manifested by the structural distortions they induce as well as the associated charge transfer from A- to D2 Ch.

Tuning the Binding Strength of Even and Uneven Hydrogen-Bonded Arrays with Remote Substituents.

We investigated the tunability of hydrogen bond strength by altering the charge accumulation around the frontier atoms with remote substituents. For pyridine···H2O with NH2 and CN substituted at different positions on pyridine, we find that the electron-withdrawing CN group decreases the negative charge accumulation around the frontier atom N, resulting in weakening of the hydrogen bond, whereas the electron-donating NH2 group increases the charge accumulation around N, resulting in strengthening of the hydrogen bond. By applying these design principles on DDAA-AADD, DADA-ADAD, DAA-ADD, and ADA-DAD hydrogen-bonded dimers, we find that the effect of the substituent is delocalized over the whole molecular system. As a consequence, systems with an equal number of hydrogen bond donor (D) and acceptor (A) atoms are not tunable in a predictable way because of cancellation of counteracting strengthening and weakening effects. Furthermore, we show that the position of the substituent and long-range electrostatics can play an important role as well. Overall, the design principles presented in this work are suitable for monomers with an unequal number of donor and acceptor atoms and can be exploited to tune the binding strength of supramolecular building blocks.

The Nature of Nonclassical Carbonyl Ligands Explained by Kohn-Sham Molecular Orbital Theory.

When carbonyl ligands coordinate to transition metals, their bond distance either increases (classical) or decreases (nonclassical) with respect to the bond length in the isolated CO molecule. C-O expansion can easily be understood by π-back-donation, which results in a population of the CO's π*-antibonding orbital and hence a weakening of its bond. Nonclassical carbonyl ligands are less straightforward to explain, and their nature is still subject of an ongoing debate. In this work, we studied five isoelectronic octahedral complexes, namely Fe(CO)6 2+ , Mn(CO)6 + , Cr(CO)6 , V(CO)6 - and Ti(CO)6 2- , at the ZORA-BLYP/TZ2P level of theory to explain this nonclassical behavior in the framework of Kohn-Sham molecular orbital theory. We show that there are two competing forces that affect the C-O bond length, namely electrostatic interactions (favoring C-O contraction) and π-back-donation (favoring C-O expansion). It is a balance between those two terms that determines whether the carbonyl is classical or nonclassical. By further decomposing the electrostatic interaction ΔVelstat into four fundamental terms, we are able to rationalize why ΔVelstat gives rise to the nonclassical behavior, leading to new insights into the driving forces behind C-O contraction.

Halogen Bonds in Ligand-Protein Systems: Molecular Orbital Theory for Drug Design.

Halogen bonds are highly important in medicinal chemistry as halogenation of drugs, generally, improves both selectivity and efficacy toward protein active sites. However, accurate modeling of halogen bond interactions remains a challenge, since a thorough theoretical investigation of the bonding mechanism, focusing on the realistic complexity of drug-receptor systems, is lacking. Our systematic quantum-chemical study on ligand/peptide-like systems reveals that halogen bonding is driven by the same bonding interactions as hydrogen bonding. Besides the electrostatic and the dispersion interactions, our bonding analyses, based on quantitative Kohn-Sham molecular orbital theory together with energy decomposition analysis, reveal that donor-acceptor interactions and steric repulsion between the occupied orbitals of the halogenated ligand and the protein need to be considered more carefully within the drug design process.

Understanding chemical reactivity using the activation strain model.

Understanding chemical reactivity through the use of state-of-the-art computational techniques enables chemists to both predict reactivity and rationally design novel reactions. This protocol aims to provide chemists with the tools to implement a powerful and robust method for analyzing and understanding any chemical reaction using PyFrag 2019. The approach is based on the so-called activation strain model (ASM) of reactivity, which relates the relative energy of a molecular system to the sum of the energies required to distort the reactants into the geometries required to react plus the strength of their mutual interactions. Other available methods analyze only a stationary point on the potential energy surface, but our methodology analyzes the change in energy along a reaction coordinate. The use of this methodology has been proven to be critical to the understanding of reactions, spanning the realms of the inorganic and organic, as well as the supramolecular and biochemical, fields. This protocol provides step-by-step instructions-starting from the optimization of the stationary points and extending through calculation of the potential energy surface and analysis of the trend-decisive energy terms-that can serve as a guide for carrying out the analysis of any given reaction of interest within hours to days, depending on the size of the molecular system.

The Nature of Hydrogen Bonds: A Delineation of the Role of Different Energy Components on Hydrogen Bond Strengths and Lengths.

Hydrogen bonds are a complex interplay between different energy components, and their nature is still subject of an ongoing debate. In this minireview, we therefore provide an overview of the different perspectives on hydrogen bonding. This will be done by discussing the following individual energy components: 1) electrostatic interactions, 2) charge-transfer interactions, 3) π-resonance assistance, 4) steric repulsion, 5) cooperative effects, 6) dispersion interactions and 7) secondary electrostatic interactions. We demonstrate how these energetic factors are essential in a correct description of the hydrogen bond, and discuss several examples of systems whose energetic and geometrical features are not captured by easy-to-use predictive models.

Secondary Electrostatic Interaction Model Revised: Prediction Comes Mainly from Measuring Charge Accumulation in Hydrogen-Bonded Monomers.

The secondary electrostatic interaction (SEI) model is often used to predict and explain relative hydrogen bond strengths of self-assembled systems. The SEI model oversimplifies the hydrogen-bonding mechanisms by viewing them as interacting point charges, but nevertheless experimental binding strengths are often in line with the model's predictions. To understand how this rudimentary model can be predictive, we computationally studied two tautomeric quadruple hydrogen-bonded systems, DDAA-AADD and DADA-ADAD. Our results reveal that when the proton donors D (which are electron-donating) and the proton acceptors A (which are electron-withdrawing) are grouped together as in DDAA, there is a larger accumulation of charge around the frontier atoms than when the proton donor and acceptor groups are alternating as in DADA. This accumulation of charge makes the proton donors more positive and the proton acceptors more negative, which enhances both the electrostatic and covalent interactions in the DDAA dimer. The SEI model is thus predictive because it provides a measure for the charge accumulation in hydrogen-bonded monomers. Our findings can be understood from simple physical organic chemistry principles and provide supramolecular chemists with meaningful understanding for tuning hydrogen bond strengths and thus for controlling the properties of self-assembled systems.

Supramolecular Self-Sorting Networks using Hydrogen-Bonding Motifs.

A current objective in supramolecular chemistry is to mimic the transitions between complex self-sorted systems that represent a hallmark of regulatory function in nature. In this work, a self-sorting network, comprising linear hydrogen motifs, was created. Selecting six hydrogen-bonding motifs capable of both high-fidelity and promiscuous molecular recognition gave rise to a complex self-sorting system, which included motifs capable of both narcissistic and social self-sorting. Examination of the interactions between individual components, experimentally and computationally, provided a rationale for the product distribution during each phase of a cascade. This reasoning holds through up to five sequential additions of six building blocks, resulting in the construction of a biomimetic network in which the presence or absence of different components provides multiple unique pathways to distinct self-sorted configurations.

Nature of Intramolecular Resonance Assisted Hydrogen Bonding in Malonaldehyde and Its Saturated Analogue.

The nature of resonance-assisted hydrogen bonds (RAHB) is still subject of an ongoing debate. We therefore analyzed the σ and π charge redistributions associated with the formation of intramolecular hydrogen bonds in malonaldehyde (MA) and its saturated analogue 3-hydroxypropanal (3-OH) and addressed the question whether there is a resonance assistance phenomenon in the sense of a synergistic interplay between the σ and π electron systems. Our quantum chemical calculations at the BP86/TZ2P level of theory show that the π charge flow is indeed in line with the Lewis structure as proposed by the RAHB model. This typical rearrangement of charge is only present in the unsaturated system, and not in its saturated analogue. Resonance in the π electron system assists the intramolecular hydrogen bond by reducing the hydrogen bond distance, and by providing an additional stabilizing component to the net bonding energy. The σ orbital interaction plays an important role in the enhanced hydrogen bond strength in MA as well. However, there is no resonance assistance in the sense of an interplay between σ charge transfer and π polarization; σ and π contribute independently from each other.

Hydrogen-Bond Strength of CC and GG Pairs Determined by Steric Repulsion: Electrostatics and Charge Transfer Overruled.

Theoretical and experimental studies have elucidated the bonding mechanism in hydrogen bonds as an electrostatic interaction, which also exhibits considerable stabilization by charge transfer, polarization, and dispersion interactions. Therefore, these components have been used to rationalize the differences in strength of hydrogen-bonded systems. A completely new viewpoint is presented, in which the Pauli (steric) repulsion controls the mechanism of hydrogen bonding. Quantum chemical computations on the mismatched DNA base pairs CC and GG (C=cytosine, G=guanine) show that the enhanced stabilization and shorter distance of GG is determined entirely by the difference in the Pauli repulsion, which is significantly less repulsive for GG than for CC. This is the first time that evidence is presented for the Pauli repulsion as decisive factor in relative hydrogen-bond strengths and lengths.