Jul 2026· Chemistry· pp.
e71403
· 0 citations· 20 references
Medicine
Abstract
We provide design principles for predicting bond exchange kinetics in acylsemicarbazide (ASC)-based systems that can be applied to tuning the properties of dynamic networks. Because of their capability of dynamic and reversible bond dissociation, ASCs are promising motifs in the design of tunable dynamic covalent networks that combine mechanical robustness with reprocessability and stability. We elucidate the factors that determine the rate of bond dissociation using density functional theory in combination with detailed kinetic studies on the mechanism of the ASC dissociation. Several ASC compounds were investigated, R1─C(═O)(H)N─N(H)─C(═O)NH─R2, with R1 methyl or phenyl, and R2 methyl, phenyl, or benzoyl, that dissociate into hydrazide and isocyanate parts. The experimentally measured dissociation rate correlates with the proton affinity of the N─H bond next to R2, which could also be used to predict relative dissociation rates a priori. Proton-transfer assistance is required for efficient bond exchange. A water molecule, but also neighboring ASCs (reactant) and hydrazides (product), lowers the activation barrier for bond dissociation considerably, likely facilitating autocatalysis that can occur in polymeric ASC networks. These findings can aid in the rational design of reversible polymers based on ASC motifs and can also be generalized for other dynamic covalent networks.
A systematic density functional theory study of hydrogen bonding, cooperative binding, and Grotthuss proton transfer in PVA/CA/H₃PO₄ proton exchange membranes is presented. Twenty-three calculations were performed at the B3LYP-D3BJ/6-31G* level using ORCA 6.1.1, encompassing geometry optimisation, potential energy surface scanning, transition state verification, nudged elastic band analysis, natural bond orbital analysis, electron localisation function mapping, and a 65-atom crosslinked wet membrane model. The esterification energy is − 12.4 kJ/mol; single H₃PO₄ binding is − 78.1 kJ/mol; and cooperative binding of two H₃PO₄ molecules reaches − 203.0 kJ/mol. The gas-phase proton transfer barrier of 37.8 kJ/mol is reduced to 19.5 kJ/mol in the fully crosslinked wet environment, with the product state 9.3 kJ/mol more stable than the reactant. NBO bond-order analysis and ELF mapping support a local hydrogen-bond-mediated proton-transfer event, representing an elementary proton-hopping step rather than direct proof of a complete long-range Grotthuss conduction mechanism. A 20-step desorption PES (+ 75.9 kJ/mol) combined with hydration analysis (ΔG = − 278.0 kJ/mol) provides a quantum-mechanical interpretation of partial acid retention. DFT-predicted IR frequencies reproduce all major peaks within 0–110 cm⁻¹.
Spontaneous deamidation and isomerization of asparagine (Asn) residues is a major pathway of nonenzymatic protein aging, where Asn-Gly-containing peptides (NG motifs) represent the most reactive sequence. In this context, the first step of isomerization is succinimide formation, which is initiated by a concerted proton-transfer and nucleophilic activation step. Although the overall mechanism is established, the detailed nature of the rate-determining succinimide formation step and the possible role of nuclear quantum effects remain unclear. Here, we combine density functional theory (DFT), intrinsic reaction coordinate (IRC) analysis, and quantitative NMR kinetics to investigate hydrogen/deuterium (H/D) substitution effects on NG isomerization in different model peptides, which represent both conformationally flexible and restricted systems. Deuteration preserves the reaction pathway and structural evolution, indicating an invariant classical reaction coordinate. However, kinetic isotope effects in the flexible peptide system reveal a mixed classical–tunneling mechanism in the rate-determining step with observable deviations from classical over-the-barrier behavior. In contrast, the conformationally restricted peptide shows suppressed tunneling contributions. These findings demonstrate that conformational accessibility modulates proton tunneling in spontaneous peptide rearrangements and extends nuclear quantum effects beyond enzymatic systems to nonenzymatic processes associated with protein aging.
Fruzsina Pilhál, Bianka Szalainé Ágoston, I. Jákli et al.· Biomolecules· 0 citations
Reliable density functional theory (DFT) methods for thermally driven cyclization reactions remain insufficiently established, particularly for systems in which proton transfer, conformational preorganization, and weak environmental effects jointly shape the energy landscape. Here, we present a systematic benchmark of DFT exchange–correlation functional/basis-set combinations against CCSD(T) reference energies for the thermal Conia–Ene cyclization, using chain length and explicit water assistance as chemically relevant probes of functional performance. Representative reaction profiles were constructed for two model substrates (hex-5-ynal and hept-6-ynal), considering pathways with and without explicit water, in both gas phase and implicit solvent. The reaction proceeds stepwise through enolization followed by cyclization, with enolization defining the intrinsic kinetic bottleneck in the water-free pathway (ca. 70 kcal mol–1). Explicit water selectively lowers this barrier by up to 30 kcal mol–1 through proton-transfer mediation, whereas the cyclization barrier is primarily controlled by chain length through transition-state preorganization; implicit solvation has only a minor energetic effect. Across 38 approximate exchange–correlation functionals and 14 basis sets, range-separated hybrids provide the most accurate and balanced description of both activation barriers and reaction energies. In particular, ωB97XD and CAM-B3LYP-D3BJ achieve near-chemical accuracy, with mean absolute errors close to 1 kcal mol–1 when combined with triple-ζ basis sets containing polarization and diffuse functions. Comparable accuracy is also achieved by the double-hybrid functionals mPW2PLYP and DSD-PBEP86, albeit at a substantially higher computational cost. Overall, this study establishes a practical CCSD(T)-referenced benchmark and identifies robust DFT protocols for modeling thermal Conia–Ene cyclizations, with expected transferability to more complex substrates and confined environments.
J. Gutiérrez-Flores, Eduardo H. Huerta, Javier Serrano Medina et al.· ACS Omega· 0 citations
Accurately predicting NMR chemical shifts of exchangeable protons in solution remains challenging because of the combined influence of solute–solvent interactions and molecular dynamics. We introduce a framework that integrates machine-learning molecular dynamics (ML-MD) with the ShiftML3 machine-learning shielding model for rapid and accurate prediction of NMR spectra in solvated molecules. Although originally developed for solids, ShiftML3 effectively captures intermolecular contributions to shielding in solution. We validate the method across a range of chemically diverse systems, including water in organic solvents, solvated alcohols, hydrogen-bonded nucleobases, glucose anomers, and alkylated acetamides. The ML-MD + ShiftML3 framework reproduces experimentally observed chemical shifts of exchangeable protons with near-quantitative accuracy, resolving subtle hydrogen-bonding and conformational effects that implicit-solvent DFT fails to capture. These results establish ML-MD + ShiftML3 as a transferable and computationally efficient way of incorporating solvation and dynamics into NMR spectroscopy, enabling realistic chemical shift predictions for flexible, hydrogen-bonded, and complex molecular systems. The authors develop a framework integrating machine-learning molecular dynamics with the ShiftML3 machine-learning shielding mode to accurately predict NMR chemical shifts of exchangeable protons in solution, outperforming DFT approaches in capturing solvation effects.
O. Socha, Jana Pavlišová, Debashree Manna et al.· Nature Communications· 2 citations
Understanding how hydration reshapes the structure and conformational flexibility of biomolecular ions is essential for connecting gas-phase spectroscopy to behavior in aqueous environments. Glycine, the simplest amino acid, exhibits rich microsolvation behavior, with competing intra- and intermolecular hydrogen-bonding motifs that evolve with hydration and temperature. Although cryogenic ion spectroscopy has provided detailed measurements of hydrated protonated glycine (GlyH+) clusters, interpreting these spectra and relating them to molecular hydration motifs remains challenging. Here, we develop a data-driven many-body potential energy function for GlyH+-H2O interactions and combine it with replica-exchange molecular dynamics to identify isomeric equilibria, and with temperature-elevated path-integral coarse-graining simulations to model GlyH+(H2O)n clusters, accounting for nuclear quantum effects. This framework captures many-body interactions with high-level ab initio accuracy and enables direct computation of infrared spectra for comparison with experiment. By applying an inverse spectral reconstruction of isomeric ensembles, we quantitatively decompose the experimental spectra into contributions from competing hydration motifs and extract their relative populations. Our results characterize the sequential formation of the first and second solvation shells, quantify the competition between intramolecular and water-mediated hydrogen bonds, and reveal temperature dependence and nuclear quantum effects. Overall, this study provides a transferable approach to understanding the hydration of biomolecular systems across scales, from gas-phase clusters to bulk aqueous solutions.
Zoe A. Solomon, R. Rashmi, Ruihan Zhou et al.· Journal of Physical Chemistr...· 0 citations
Halogen bonding (XB) is often analyzed in terms of isolated dimers, yet under realistic solution conditions, it coexists with a dense, rapidly fluctuating network of weaker contacts whose net effect on bond strength is difficult to quantify. Here, we combine gas-phase quantum-chemical calculations with explicit-solvent ab initio molecular dynamics (AIMD) in chloroform to dissect how specific noncovalent interactions modulate the I···N halogen bond in ortho-, meta-, and para-C6F4I2···HMTA complexes. Gas-phase DFT, Quantum Theory of Atoms in Molecules (QTAIM), Natural Bond Orbital (NBO), and SAPT0 analyses show that the intrinsic I···N bond in the three isomers is relatively strong and nearly degenerate, with equilibrium distances around 2.83 Å and very similar electronic descriptors. In contrast, AIMD in CHCl3 reveals that the solution-phase geometry reflects a dynamic balance between frequent, short-lived C-H···N contacts to HMTA, which act anticooperatively and lengthen the halogen bond by ≈0.02-0.05 Å, and less populated but more cooperative donor-side C-H···I and C-H···F contacts to the C6F4I2 fragment, which shorten it by up to ≈0.05 Å. A contact-resolved and microstate-based analysis shows that each isomer samples a small number of recurrent solvation motifs with characteristic patterns of C-H···N/C-H···I/C-H···F coordination, and that the relative populations of these motifs control the average I···N distance in solution. Targeted cluster calculations containing only one additional interaction at a time demonstrate that extra C-I···N halogen bonds are intrinsically anticooperative toward the primary I···N bond, whereas C-H···F hydrogen bonding, π···π stacking, and especially C-H···I contacts provide genuine cooperative reinforcement, in line with the trends observed in AIMD. Together, these results establish a quantitative solution-phase hierarchy of cooperative and anticooperative motifs around σ-hole donors and rationalize why gas-phase dimers systematically overestimate halogen-bond robustness relative to chloroform solution, where anticooperative C-H···N hydrogen bonding is ubiquitous. More broadly, the combination of explicit-solvent AIMD with contact-resolved and microstate-based analysis provides a transferable framework for dissecting environmental cooperativity in halogen-bonded and other σ-hole-driven assemblies in liquid phases.
D. V. Krutin, A. Titova, M. Kaplanskiy et al.· Journal of Physical Chemistr...· 0 citations
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