Conformational landscapes of alkali metalated N-acetylhexosamines: insights from machine learning-assisted ab initio methods and validated by cryogenic infrared photodissociation spectroscopy.
Aug 2026· Physical Chemistry, Chemical Physics - PCCP· 0 citations· 39 references
Medicine
Abstract
The complex structural effects of metal ion binding in glycans remain a topic of significant scientific interest. In this study, we implement a machine learning-driven workflow utilizing SchNet-based neural network potentials (NNPs) to efficiently map the conformational space of neutral and metalated N-acetylhexosamines (HexNAc) with near-first-principles accuracy. By constructing an extensive database of local minima for all 64 HexNAc isomers, we identify critical trends in how alkali metal ions modulate carbohydrate conformation. Our NNP-driven structural search scheme, validated against cryogenic infrared photodissociation (IRPD) spectra, successfully identifies the specific low-energy conformers responsible for experimentally observed vibrational signatures. Notably, our results reveal a diverse set of structural and energetic trends that vary significantly across the different metalated HexNAc systems. These findings underscore the necessity of explicit, automated structure searching, as the non-intuitive coordination environments of metal ions preclude the use of generalized conformational rules.
Proton-coupled electron transfer (PCET) mediated by hydroquinone and related molecules is key to natural and artificial energy conversion. The reactivity of these molecules depends on their bond dissociation free energy (BDFE), but studying the relationship between structure and thermochemistry across this chemical space has been limited by challenging experimental setup and high computational expense. Here, we present the first use of the AIMNet2 neural network potential to calculate average BDFE (BDFEavg) values for the 2H+/2e− dehydrogenation of about 200 000 hydroquinone-like compounds, including vicinal diamines, diols, and dithiols. Benchmarking against DFT calculations for 168 substituted ortho-phenylenediamines (opda) shows good agreement (R2 ∼ 0.84). Our analysis finds that the BDFEavg of diamines ranges from 50 to 80 kcal mol−1 and can be systematically tuned by modifying the backbone and N-substitution: electron-withdrawing groups raise BDFEavg by up to 15 kcal mol−1, while lower aromaticity in furan and thiophene backbones decreases BDFEavg by approximately 10 kcal mol−1 compared to the phenyl systems (∼65 kcal mol−1). Validation through cyclic voltammetry and reactivity studies with quinone oxidants for selected compounds supports the computational results. This extensive thermochemical database and a web-based prediction tool developed as a result of this work will offer valuable resources for designing PCET reagents for catalysis, energy storage, and biomedical uses.
Rajdeep Sarma, Yiwen Wang, David D Hebert et al.· Chemical Science· 0 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
This study illustrates how subtle residue-localized conformational bias can affect the overall protein conformational dynamics influencing protein-protein interactions that are important for cellular functions and related to diseases.
Abir Ben Bouzayene, M. Sai, Alexis Jouin et al.· Angewandte Chemie· 0 citations
The convergence of docking, dynamics, and free-energy results prioritized PM2, PM3, and PM4 as promising MAP3K8 hit candidates, which require further experimental validation and lead optimization.
M. Islam, A. Iqbal, M. A. Ali et al.· Molecular diversity· 0 citations
A design principle is proposed for advanced metal nitride HEDMs: prioritizing high nitrogen-to-metal ratios, light metal elements, and structures wherein nitrogen atoms are spatially separated by the metal matrix, which minimizes N-N bonds and favors dominant M-N bonding.
Yaozhong Liu, Huifang Du, Caimu Wang et al.· Chinese Physics B· 0 citations
An equimolar N-methylacetamide-water (NMA-W) mixture was re-examined by combining molecular dynamics (MD) simulations, DFT-based Natural Bond Orbital (NBO) and Atoms-in-Molecules (AIM) analyses, and data-driven reconstruction of previously reported neutron scattering functions of the NMA-W liquid. MD simulations, using an AMBER-based force field for NMA and the SPC/E model for water, reproduce reasonably well the experimental structure factors and pair correlation functions of the liquid. In parallel, a Random Forest Regressor is employed as a nonparametric data-driven reconstruction tool, showing that the main features of the structural data can be represented as a continuous numerical representation of the scattering vector Q, providing a continuous numerical representation for comparison purposes. Three representative NMA-water clusters previously identified as the most probable local arrangements governing the liquid structure are further analyzed using NBO and Atoms-in-Molecules (AIM) approaches. The analysis provides additional information on hydrogen-bond electronic structure, including charge-transfer effects, electron density at bond critical points, and topological characteristics of intermolecular interactions. Comparison with MD-derived lifetimes shows that stronger electronic interactions do not always correspond to longer-lived hydrogen bonds, reflecting the role of local network topology and dynamical fluctuations.
H. Abdelmoulahi, Sahbi Trabelsi, S. Bouazizi et al.· Journal of Physical Chemistr...· 0 citations
