Energy Surface Analysis Research Articles

Probing the Conformational Ensemble of the Amyloid Beta 16-22 Fragment with Parallel-Bias Metadynamics.

Aβ(16-22) is a segment of the Alzheimer's-related β-amyloid peptide that plays a crucial role in its aggregation. This study applies well-tempered parallel-bias metadynamics to investigate the impact of several denaturants and osmolytes on the conformational ensembles of both termini-capped and uncapped Aβ(16-22) monomers. Comparison of the different sets of collective variables in the metadynamics bias shows that using the set of backbone torsional angles results in better and faster convergence of simulations than employing more general structural characteristics of the short peptide. The equilibrium conformational ensembles of the peptides are characterized in pure water and in the presence of TMAO, urea, guanidinium chloride, and trifluoroethanol. In particular, trifluoroethanol and TMAO are found to increase the population of compact peptide conformations, whereas urea and guanidinium chloride favor extended structures. The analysis of the free energy surfaces in the presence of various substances with a comparison of the behavior of the capped and uncapped peptide forms reveals the role of different types of intrapeptide interactions such as salt bridges, hydrophobic contacts, and hydrogen bonds in stabilization of the compact or extended structures. As compounds reducing the abundance of the compact states of Aβ(16-22) and other disordered peptides are likely to suppress their amyloid fibril formation, simulations in the systems with this short peptide may be useful for the virtual screening of such compounds.

Dynamics of Lanthanide(III) complexes from crystallographic data and computational studies

In this study we take advantage of the large body of X-ray data reported for lanthanide complexes, as well as their similar coordination chemistry properties, to gain insight on the dynamic processes involving λ ↔ δ configurational changes leading to isomer interconversion. The analysis of X-ray data reveals that different donor groups are characterized by Gaussian distributions of the dihedral N–C–X–Y angles ϕ. In the case of ethylenediamine groups (X = C; Y = N) Gaussian distributions are very narrow, while acetates (X = C; Y = O) provide very broad distributions. The analysis of the potential energy surfaces (PESs) using DFT reveals that ethylenediamine groups are characterised by well-defined deep energy minima, while those of acetate groups are rather swallow. Other donor groups like acetamide, pyridine or phosphinate show intermediate Gaussian distributions with respect to ethylenediamine and acetates. The PESs were fitted to a potential incorporating quadratic, cubic and quartic terms. The quadratic force constants k11 obtained for the different donor types follow the trend of the full width at half maxima (FWHM) of Gaussian distributions obtained from X-ray data. The k11 values are very similar for a given donor group, while the anharmonic cubic (k111) and quartic (k1111) force constants vary significantly depending on the environment of the donor group. Overall, this work demonstrates that the analysis of X-ray crystallographic data in lanthanide complexes can provide very useful information on their coordination chemistry preferences and dynamic processes.

Quantum Chemical Approaches for Manipulation and Evaluation of Intracage Microelectric Field Strength of Molecular Containers in Y@C64 and Y@C64X4 (X = Cl, F, and H, Y = NH4Cl, H3O-Cl, and 2H2O).

The effect of an oriented external electric field (EEF) on materials has led to the ongoing development, which stimulates us to consider whether intracage microelectric fields (IMEFs) can be used to substitute for the EEF. Focusing on the manipulation and evaluation of the IMEF of asymmetric molecular containers, the host-guest compounds of interesting pineapple-shaped Y@C64X4 (X = vacant, Cl, F, and H; Y = NH4Cl, H3O-Cl, and 2H2O) are theoretically constructed and the strength of the IMEF was evaluated by the intrapotential energy surface analysis by using the point charge (q = +1) scanning method. Interestingly, the left and right halves of each cage are like two IMEFs connected in reverse series. Both the addition of four X atoms and the orientation of the guest can sensitively influence the IMEF's strengths and directions of both half cages and further determine the entire cage's IMEF. Subsequently, the IMEF can sensitively change the binding characteristics and properties of the guest species. Therefore, the manipulation and evaluation of the IMEF can be achievable. This work may provide support for an asymmetric molecular container with an IMEF to manipulate the novel structural and chemical bond characteristics of the guest species.

Solvent Effect on Dative and Ionic Bond Strengths: A Unified Theory from Potential Analysis and Valence-Bond Computations.

Solvent molecules interact with a solute through various intermolecular forces. Here we employed a potential energy surface (PES) analysis to interpret the solvent-induced variations in the strengths of dative (Me3NBH3) and ionic (LiCl) bonds, which possess both ionic and covalent (neutral) characteristics. The change of a bond is driven by the gradient (force) of the solvent-solute interaction energy with respect to the focused bond length. Positive force shortens the bond length and increases the bond force constant, leading to a blue-shift of the bond stretching vibrational frequency upon solvation. Conversely, negative force elongates the bond, resulting in a reduced bond force constant and red-shift of the stretching vibrational frequency. The different responses of Me3NBH3 and LiCl to solvation are studied with valence bond (VB) theory, as Me3NBH3 and LiCl are dominated by the neutral covalent VB structure and the ionic VB structure, respectively. The dipole moment of an ionic VB structure increases along the increasing bond distance, while the dipole moment of a neutral covalent VB structure increases with the decreasing bond distance. The roles of the dominating VB structures are further examined by the geometry optimizations and frequency calculations with the block-localized wavefunction (BLW) method.

Study of heavy metals adsorption using a silicate-based material: Experiments and theoretical insights

Heavy metal toxicity in water is a serious problem with harmful effects on human health and the ecosystem. This research studied a silicate-based material as an adsorbent for removing four heavy metals from aqueous solutions. The target metal pollutants selected include manganese (Mn2+), copper (Cu2+), cobalt (Co2+), and zinc (Zn2+). First, theoretical tools including potential energy surface analysis, Natural Population Analysis, AIM, Wiberg Bond Index, QTAIM, and topological methods offer profound insights into the nature of interactions present in the Mg2O8Si3M (M = Mn2+, Cu2+, Co2+, Zn2+) clusters. Second, the synthesis and characterization of eco-friendly hydrated amorphous magnesium silicate (MgOSiO2nH2O) was developed. Last, a simple kinetic adsorption test was applied to assess the material selectivity towards heavy metals and support theoretical results. The kinetic adsorption study was analyzed through the pseudo-first and second-order kinetics, Elovich, and the intraparticle diffusion models. The theoretical analysis of the adsorption energies indicates that the adsorption of four metal ions on the Mg2O8Si3 surface is energetically favorable in all cases. The material displayed the following adsorption sequence: Cu2+ (59 mg g-1) > Zn2+(25 mg g-1) ≈ Co2+ (23 mg g-1) > Mn2+ (15 mg g-1). This knowledge can then be used to design and optimize low-cost silicate-based materials for effective heavy metal removal, contributing to efforts to address environmental pollution and protect public health.

Solvent effect, spectral (SERS and UV-Vis) and adsorption analysis of Gliadel (GL) anticancer drug with Ag/Au loaded silica nanocomposites

Drug delivery devices reduce drug molecule toxicity and nanostructure can be used to targeted drug delivery. A quantitative analysis of the interaction behavior of Gliadel (GL) with Ag/Au…SiO2 presented in this study in order to minimize drug molecule toxicity. The stabilized structure with the lowest energy conformer of GL in both the gas/water phases has been examined using potential energy surface (PES) analysis, after which the structure was optimized. In the reactivity study, silver/gold loaded silica nanocomposites formed by GL exhibit an increasing electrophilicity index, giving a characteristic to the systems. UV–Vis. analysis was studied to assess the excited state of the investigated complexes using time-dependent density function theory (TD-DFT) in both gas and water phases. The electron transfer within a molecule is determined by Frontier Molecular Orbitals, or FMOs. The charge distribution within the molecule was examined using a color-coded graphic representation of the molecular electrostatic potential (MEP) map. To the extent that to sort out whether a molecule was desirable for use as a medicine, the drug delivery procedure took into account its absorption, distribution, metabolism, and excretion (ADME) qualities. Finally, molecular docking with the selected proteins was examined using the complexes and pure.

Unveiling the molecular insights of 2-(carboxymethyl) benzoic acid: A density functional theory approach towards structural and biological attributes

Nowadays density functional theory (DFT) is one of the best methods to explore the vibrational modes and structure of the biological system. Quantum mechanical calculations are performed using gas phase and different solvents (DMSO, methanol and water). The derived global reactive parameters, structural and topological study provides the clear insight of the 2-(Carboxymethyl) benzoic acid. Depth studies of DFT proves the existence of hydrogen bonds between donor and acceptor in the compound, which is supportive for the biological applications. In this paper, different experimental and computational simulated FT-IR, FT-Raman, UV–Vis spectral studies are used to explicate vibration assignments of the 2-(Carboxymethyl) benzoic acid. Experimentally observed vibrational frequency is compared with theoretically simulated spectrum. B3LYP method with 6–311++G (d, p) basis set is used in DFT to optimize the 2-(Carboxymethyl)benzoic acid structure. The most stable lower energy conformer is identified using potential energy surface (PES) analysis using Gaussian 16 W software. ESP, HOMO-LUMO, NBO, and QTAIM calculations have evinced an adequate electronic characterization of 2-(Carboxymethyl) benzoic acid. Further, van der Waals and steric interactions among 2-(Carboxymethyl) benzoic acid have been discussed with the help of RDG study. Hirshfeld surface studies establish the existing various interaction among molecules and total packing arrangement of the crystal structure. Due to the high biological activity score, 2-(Carboxymethyl) benzoic acid is a good therapeutic candidate. Lipophilicity analysis of 2-(Carboxymethyl)benzoic acid clearly explicates the bioactivity properties and its effective drug applications. Further, molecular docking investigates that the compound can be used as anticancer medication. The detailed DFT study of the 2-(Carboxymethyl) benzoic acid justified its biological applications of the present communication. The calculated NLO parameters of 2-(Carboxymethyl)benzoic acid evidenced for good efficacy in diverse filed application has been discussed.

DFT investigation of the DDQ-catalytic mechanism for constructing C-O bonds.

In this study, we investigated the photo-catalytic mechanisms for the construction of C-O bonds from arenes (benzene, 2',6'-dimethyl-[1,1'-biphenyl]-2-carboxylic acid, or 2,4-dichloro-1-fluorobenzene), catalyzed by 2,3-dichloro-5,6-dicyano-p-benzoquinone (DDQ). All the structures for the Gibbs free surfaces were calculated at the M06-2X-D3/ma-def2-SVP level in the SMD solvent model. Also, TDDFT calculations of DDQ were performed at the PBE1PBE-D3/ma-def2-SVP level in the SMD solvent model. The computational results indicated that DDQ, serving as a photo-catalyst, would be excited under visible light of 450 nm, aligning well with experimental observations as reflected in the UV-vis spectrum. Gibbs free energy surface analyses of the three reactions suggested that the path involving 3DDQ* activating the reactant (-COOH, H2O, or CH3OH) is favorable. Additionally, the role of O2 was investigated, revealing that it could facilitate the recycling of DDQ by lowering the energy barrier for the conversion of the DDQH˙ radical (not DDQH2) into DDQ. The use of ρhole and ρele can reveal the photo-catalytic reaction and charge transfer processes, while localized orbital locator isosurfaces and electron spin density isosurface graphs were employed to analyze structures and elucidate the single electron distribution. These computational results offer valuable insights into the studied interactions and related processes, shedding light on the mechanisms governing C-O bond formation from arenes catalyzed by DDQ.

Predictive study, using density functional theory and time dependent functional theory, on the structure-property quantification of methylene blue and methyl red dyes for the application in organic solar cells

In this work, two organic materials as dyes, namely, methylene blue (MB) and methyl red (MR), have been proposed to play the role of the electron donor in organic photovoltaic (OPV) cells. We use the PCBM as a well-known electron acceptor. The density functional theory (DFT) method has been used to determine the electrostatic potential and the frontier molecular orbitals (FMO), of the methylene blue (MB) and the methyl red (MR) compounds. Nonlinear optical (NLO) descriptors have been determined for the two compounds. The potential energy surface analysis has been performed by the DFT method using the exchange and correlation of Becke, Lee, Yang, and Parr Gradient Corrected Functional (B3LYP) with the standard 6-31G(d) base. We have performed another theoretical study using quantum time-dependent density functional theory (TD-DFT) on both MB and MR as organic dyes to determine their UV-Vis spectra. The results of the energy gap, chemical hardness, dipole moment, and hyperpolarizability show that MB may be chemically more reactive Than MR. The present work has proposed a bilayer organic photovoltaic (OPV) cell to contribute to the valorization of the two dyes as solar materials. The developed photovoltaic cell project has used electrical and energetic parameters that can describe the OPV cell based on ([MB or MR]: PCBM). Open-circuit voltage (Voc), excitation energy, and oscillator strength have been theoretically determined. The results of the present work showed a remarkably high open circuit voltage, especially in the case of methyl red (1.55 V) more than in the case of the methylene blue (0.84 V) so that both of the two dyes can be a good candidate for organic solar cells.

Exploring the interaction of phytochemicals from Hibiscus rosa-sinensis flowers with glucosidase and acetylcholinesterase: An integrated in vitro and in silico approach

Targeting multiple factors such as oxidative stress, alpha glucosidase and acetylcholinesterase (AChE) are considered advantageous for the treatment of diabetes and diabetes associated-cognitive dysfunction. In the present study, Hibiscus rosa-sinensis flowers anthocyanin-rich extract (HRA) was prepared. Phytochemical analysis of HRA using LC-ESI/MS/MS revealed the presence of various phenolic acids, flavonoids and anthocyanins. HRA showed in vitro antioxidant activity at low concentrations. HRA inhibited all the activities of mammalian glucosidases and AChE activity. The IC50 value of HRA for the inhibition of maltase, sucrase, isomaltase, glucoamylase and AChE was found to be 308.02 ± 34.25 µg/ml, 287.8 ± 19.49 µg/ml, 424.58 ± 34.75 µg/ml, 408.94 ± 64.82 µg/ml and 264.13 ± 30.84 µg/ml, respectively. Kinetic analysis revealed mixed-type inhibition against all the activities except for glucoamylase (competitive) activity. In silico analysis confirmed the interaction of two active constituents cyanidin 3-sophoroside (CS) and quercetin 3-O-sophoroside (QS) with four subunits, n-terminal and c-terminal subunits of human maltase-glucoamylase and sucrase-isomaltase as well as with AChE. Molecular dynamics simulation, binding free energy calculation, DCCM, PCA, PCA-based free energy surface analysis ascertained the stable binding of CS and QS with target proteins studied. HRA could be used as complementary therapy for diabetes and cognitive improvement.

Partial Oxidation of Methane to Methanol by Using Molecular O2 on Pd2+ Catalyst: An Insight from Theory

AbstractThe partial oxidation of methane to methanol using cationic Pd2 dimers is investigated by employing density functional theory (DFT) method. We used B3PW91 functional for geometry optimization, and frequency calculations of all species involved in [Pd2]++O2+2CH4 reaction. Furthermore, a density‐fitting triple zeta valence with single‐polarization (def2TZVP) is used in the calculation to determine the atomic orbitals of the atoms. We oxidized Pd2+ to [Pd2O2]+ using O2 and performed possible partial oxidation of methane to methanol on [Pd2O2]+ and [Pd2O]+ and explored various intermediates and transition states on the potential energy surface (PES) diagram. From Potential Energy Surface (PES) analysis, it is found that the [Pd2O2]+ in doublet spin state multiplicity (SM=2) following radical mechanism is the more preferred pathway for methane to methanol conversion.

Insilico molecular modelling to identify PDK-1 targeting agents based on its protein–protein docking interaction

PDK1, an attractive cancer target that downstreams 23 other kinases towards cell growth, survival and metabolism has gaining attention due to allosteric effect of ligands bound to it. Generally, the drug design strategy using pharmacophores is either a single protein structure or ensemble or ligand-based. Apart from these methods, yet another new approach of protein–protein docking with state of art computational tool like Schrodinger Suite to generate pharmacophores based on the interacting partners of the protein is proposed in this work. The structure-based pharmacophoric features were picked up from docking the ten interacting partners of PDK1 and screened against the Enamine libraries containing protein–protein interacting compound collection, advanced, protein mimetic and allosteric compounds. High throughput virtual screening against the PIF pocket of PDK1 yields an indole scaffold. The identified indole derivative is proposed to be a strong activator that binds in the protein–protein interaction site of PDK1 which was further confirmed by molecular metadynamics simulations, free energy surface analysis and MM-GBSA calculations. Thus, the pharmacophores generated by the interacting proteins for PPI can facilitate the virtual screening in structure-based drug discovery of similar therapeutic targets. Communicated by Ramaswamy H. Sarma

Multi-spectroscopic, thermodynamic and molecular simulation studies on binding of pyrroloquinoline quinone with DNA: coexistence of intercalation and groove binding modes

The interaction between enzyme-like pyrroloquinoline quinone (PQQ) and calf-thymus DNA (CT-DNA) has been investigated by means of multi-spectroscopic (UV-Vis, fluorescence and circular dichroism), isothermal titration calorimetric (ITC), viscometry and molecular docking and metadynamics simulation techniques. Absorption spectral data suggested the formation of a PQQ/CT-DNA complex, which quenched the fluorescence of PQQ via the dynamic quenching process. The results of CD spectral studies coupled with viscosity measurements, competitive binding assays with Hoechst 33258 and ethidium bromide (EB), KI quenching experiments, gel electrophoresis and DNA melting studies indicated groove binding mode of interaction of PQQ with CT-DNA. ITC experiment revealed that the complex formation is a spontaneous process (ΔGo < 0) with a binding constant of 1.05 × 104 M−1. The observed ΔHo < 0 and ΔSo < 0 pointed out that the complex is stabilized by van der Waals forces along with H-bonding interactions. The outcomes of molecular docking and simulation studies confirmed the binding of PQQ with DNA. The free energy surface (FES) analysis pointed out the existence of an equilibrium between partial intercalation and groove binding modes, which is in good agreement with the competitive binding assays. Communicated by Ramaswamy H. Sarma

Multi-spectroscopic and molecular simulation methods of analysis to explore the mode of binding of Mebendazole drug with calf-thymus DNA

UV–vis, fluorescence, circular dichroism (CD) and 1H NMR spectroscopic techniques have been employed to explore the mode of binding of Mebendazole (MBZ) drug with calf thymus DNA (CT-DNA). UV–vis and fluorescence spectral studies suggested a complex formation between the drug and nucleic acid. The fluorescence of MBZ was found to enhance upon binding with CT-DNA through a ground state complex formation with Kb in the order of 104 M−1. The thermodynamic aspects indicated that the complex formation is a spontaneous process and an entropy-driven one. ΔH0 > 0 and ΔS0 > 0 revealed that hydrophobic interaction plays a dominant role in the stabilization of the complex. Competitive dye displacement assays with ethidium bromide (EB) and Hoechst 33258 dyes and viscosity measurements pointed out that MBZ binds with CT-DNA via intercalation mode, which is confirmed by CD and 1H NMR spectral studies as well as denaturation studies. Molecular docking analysis could not match well with the experimental results. However, molecular simulation studies and the resultant free energy surface (FES) analysis clearly showed that the benzimidazole ring of MBZ intercalated between the base pairs of the nucleic acid, which is in excellent agreement with the results of the various biophysical experiments.

Intercalation of anticancer drug Palbociclib with calf-thymus DNA: new insights from molecular spectroscopic, molecular dynamic simulations and cleavage studies

The interaction between the anti-cancer drug Palbociclib (PAL) and calf-thymus DNA (CT-DNA) was investigated using various biophysical techniques in a physiological buffer (pH 7.4). It was found that PAL intercalated into the base pairs of CT-DNA as evidenced from the results of UV-Vis, fluorescence, circular dichroism (CD), competitive binding assay with ethidium bromide (EB) and Hoechst 33258, KI quenching study, the effect of denaturing agent and viscosity measurements. The magnitude of binding constants (106 M−1) at different temperatures suggested strong binding between PAL and CT-DNA during complexation. The observed ΔHo > 0 and ΔSo > 0 indicated that the binding process is primarily driven by hydrophobic interactions. Molecular docking studies indicated partial intercalation of pyridopyrimidine ring between the base pairs of DNA. Free energy surface (FES) analysis derived from metadynamics simulation studies revealed the PAL-induced cleavage of DNA, which was confirmed by gel electrophoresis experiments. Communicated by Ramaswamy H. Sarma

Zr isotopes as a case study for intertwined quantum phase transitions

The scenario of intertwined quantum phase transitions (IQPTs) is identified in the Zr isotopes with neutron numbers 52–70, and shown to involve both a crossing of normal and intruder configurations and a shape-evolution within each configuration. Using the framework of the interacting boson model with configuration mixing, this situation is demonstrated by a quantum analysis of the spectra, E2 transition rates, order parameters, symmetry and configuration content of the wave functions and a classical analysis of energy surfaces.

Tuning the competition between photoisomerization and photothermy in biomimetic cyclocurcumin analogues

We report the synthesis and photophysical characterization of biomimetic D-A-D’ cyclocurcumin derivatives, which can potentially be used in light activated chemotherapy. Particularly we highlight that both the donor (D) and acceptor (A) groups significantly influence the photophysical response of the chromophore inducing strong bathochromic shift with D/A strength increase and notable fluorescence quantum yield enhancement with donor strength increase. More important, the nature of the acceptor group (oxo or malonitrile) dramatically modifies the outcome in non-radiative deactivation channels. Indeed, while compounds functionalized with an oxo-moiety undergo ethylenic E → Z photoisomerization, the one bearing a malonitrile group leads exclusively to other non-adiabatic internal conversion channels which much favor photothermal conversion as no isomerization of the ethylenic double bond was observed. The tuning of the photophysical properties and the alteration of isomerization vs photothermal conversion is rationalized through the analysis of the potential energy surfaces along the most relevant degrees of freedom and shows a competitive pathway over malonitrile rotation. Our results offer novel perspective in oxygen-independent light activated chemotherapy and in the control of photochemical processes in biomimetic chromophores.

Preparation, characterization, and crystal structures of novel sophocarpine salts with improvements on stability and solubility

Crystal engineering has proved to be an effective and reliable approach to tailor the physicochemical properties of active pharmaceutical ingredients. In this work, three novel sophocarpine salts were prepared and reported, named sophocarpine-hesperetin (SC-HES), sophocarpine-L-(-) malic acid monohydrate (SC-LMA MH), and sophocarpine-p-hydroxybenzoic acid monohydrate (SC-PHBA MH). The crystal structures of the salts were confirmed by infrared spectroscopy and single crystal X-ray diffraction. SC-HES exhibited a laminated molecular stacking structure, SC-LMA MH formed a wavy layered structure, while sophocarpine molecules filled in the voids of the reticular structure to form the 3D structure of the SC-PHBA MH. Thermal analysis shows that after salification, the melting point of the compound increased from 78°C to over 120°C, overcoming its low melting point. Lattice energy and Hirshfeld surface analysis indicated that lower lattice energy provides better thermal stability of the crystal and intermolecular hydrogen bonds (O–H···O and N→H···O) play a key role in the construction of the crystal structures. In addition, the water solubility and hygroscopicity of the three salts were characterized and discussed, with SC-HES exhibiting satisfying physical stabilities and hygroscopicity, and SC-LMA MH achieving 6.7 times solubility than the free base, which provides viable options for solid dosage form development of the drug.

Interplay of Dual-Proton Transfer Relay to Achieve Full-Color Panel Luminescence in Excited-State Intramolecular Proton Transfer (ESIPT) Fluorophores.

A new design was applied for the facile synthesis of pure organic photoluminescent molecules with dual excited-state intramolecular proton transfer (ESIPT) sites. In this novel class of emitters, full-color panel emission from blue, green, and yellow to red, including white light, can be achieved in different solvents as modulated by the enol-keto(1st)-keto(2nd) tautomer emissions. A comprehensive transient photophysical study verifies that keto(1st) and keto(2nd) have a precursor (<0.8 ps)-successor (∼20 ps)-relayed absorbance relationship, and then a fast equilibrium between the two is established, resulting in dual emissions in the nanosecond scale (∼1900 ps). Through the research on copper ions' selective PL response, the dual-ESIPT mechanism was further verified; in addition, the study of solid-state PL changes upon the stimulus of organic vapor manifests the potential application sensitivity of the molecules as dual-ESIPT sensors. Theoretical results including reaction potential energy surface analyses manifest the fact that dual-proton transfer goes along a sequential route with a smaller energy barrier, firmly supporting the experimental results. An intrinsic system that undergoes intramolecular double proton relayed transfer is thus established for the achievement of much broadened optical responses and full-color display, providing reference for the design and application of advanced dual-ESIPT optical materials.

Uncovering the Mechanism of Thermally Activated Delayed Fluorescence in Coplanar Emitters Using Potential Energy Surface Analysis

Planarized emitters exhibiting thermally activated delayed fluorescence (TADF) have attracted attention due to their narrow emission spectra, improved photostability, and high quantum yields, but with large singlet-triplet energy gaps (ΔEST) and no heavy atoms, the origin of their TADF remains a subject of debate. Here we prepare two isomeric, coplanar donor-acceptor compounds, with HMAT-2PYM performing dual TADF and room-temperature phosphorescence but with HMAT-4PYM exhibiting only prompt fluorescence. Although conventional TADF design principles suggest that neither isomer should exhibit TADF, we reveal differences in the excited state potential energy surfaces that enable spin-flip processes in only one isomer. We also find that hydrogen bonding is absent between the planar units of these emitters, despite earlier claims of intramolecular hydrogen bonding in similar compounds. Overall, this work demonstrates that potential energy surface analysis is a practical strategy for designing coplanar TADF materials that might otherwise be overlooked by conventional TADF design metrics.