Quantifying Interactions and Solvent Effects Using Molecular Balances and Model Complexes

Elmi, Alex; Cockroft, Scott L.

doi:10.1021/acs.accounts.0c00545

Cited by 35 publications

(27 citation statements)

References 79 publications

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“…Moreover, since the position of a conformational equilibrium can often be determined with high accuracy from a single NMR spectrum, the measurement of very weak interactions at low mM concentrations is facilitated across a wide range of solvents. Accordingly, molecular balances have been used to evaluate diverse interactions [39–54] and solvent effects [35, 37, 38, 55–59] . To date, molecular balance studies of H‐bonding in amides [60, 61] or alcohols [62] have been confined to non‐competitive apolar solvents.…”

Section: Figurementioning

confidence: 99%

“…To date, molecular balance studies of H‐bonding in amides [60, 61] or alcohols [62] have been confined to non‐competitive apolar solvents. Meanwhile, systematic examinations of solvent effects have been limited to molecular balances lacking H‐bonding motifs [31, 35, 39] …”

Section: Figurementioning

confidence: 99%

“…[24,29,30] Molecular balances present an alternative to supramolecular complexation for the study of molecular recognition. [33][34][35][36][37][38] Molecular balances exploit conformational changes that report the strength of intramolecular interactions that are present in one conformation but absent in another (e.g. Figure 1).…”

mentioning

confidence: 99%

“…Accordingly, molecular balances have been used to evaluate diverse interactions [39][40][41][42][43][44][45][46][47][48][49][50][51][52][53][54] and solvent effects. [35,37,38,[55][56][57][58][59] To date, molecular balance studies of H-bonding in amides [60,61] or alcohols [62] have been confined to non-competitive apolar solvents. Meanwhile, systematic examinations of solvent effects have been limited to molecular balances lacking H-bonding motifs.…”

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Dissecting Solvent Effects on Hydrogen Bonding

et al. 2022

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The experimental isolation of H‐bond energetics from the typically dominant influence of the solvent remains challenging. Here we use synthetic molecular balances to quantify amine/amide H‐bonds in competitive solvents. Over 200 conformational free energy differences were determined using 24 H‐bonding balances in 9 solvents spanning a wide polarity range. The correlations between experimental interaction energies and gas‐phase computed energies exhibited wild solvent‐dependent variation. However, excellent correlations were found between the same computed energies and the experimental data following empirical dissection of solvent effects using Hunter's α/β solvation model. In addition to facilitating the direct comparison of experimental and computational data, changes in the fitted donor and acceptor constants reveal the energetics of secondary local interactions such as competing H‐bonds.

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Section: Figurementioning

confidence: 99%

Section: Figurementioning

confidence: 99%

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confidence: 99%

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confidence: 99%

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Dissecting Solvent Effects on Hydrogen Bonding

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“…13 The joint experimental and computational investigations by Cockroft and coworkers further stress the difficulties of rec-onciling theory and experiment when taking the solvent into consideration. 14,15 They have, for instance, demonstrated that NCIs are strongly attenuated in a solvated environment. 16 Despite the intense efforts associated with developing a posteriori dispersion corrections [17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34] or with reducing the cost of wavefunction-based methods, [35][36][37][38][39][40][41] the finite-temperature description of competing NCIs remains coarse if the solvent is represented as a continuum.…”

Section: Introductionmentioning

confidence: 99%

Assessing the persistence of chalcogen bonds in solution with neural network potentials

Juraskova,

Celerse,

Laplaza

et al. 2022

Preprint

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Non-covalent bonding patterns are commonly harvested as a design principle in the field of catalysis, supramolecular chemistry and functional materials to name a few. Yet, their computational description generally neglects finite temperature and environment effects, which promote competing interactions and alter their static gas-phase properties. Recently, neural network potentials (NNPs) trained on Density Functional Theory (DFT) data have become increasingly popular to simulate molecular phenomena in condensed phase with an accuracy comparable to ab initio methods. To date, most applications have centered on solid-state materials or fairly simple molecules made of a limited number of elements. Herein, we focus on the persistence and strength of chalcogen bonds involving a benzotelluradiazole in condensed phase. While the tellurium-containing heteroaromatic molecules are known to exhibit pronounced interactions with anions and lone pairs of different atoms, the relevance of competing intermolecular interactions, notably with the solvent, are complicated to monitor experimentally but also challenging to model at an accurate electronic structure level. Here, we train a direct and baselined NNPs to reproduce hybrid DFT energies and forces in order to identify what are the most prevalent non-covalent interactions occurring in a solute-Cl --THF mixture. The simulations in explicit solvent highlight the clear competition with chalcogen bonds formed with the solvent and the short-range directionality of the interaction with direct consequences for the molecular properties in the solution. The comparison with other potentials (e.g., AMOEBA, direct NNP and continuum solvent model) also demonstrates that baselined NNPs offer a reliable picture of the non-covalent interaction interplay occurring in solution.

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Solvation free energy in governing equations for DNA hybridization, protein–ligand binding, and protein folding

Harmon,

Bui,

Espejo

et al. 2024

FEBS Open Bio

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This work examines the thermodynamics of model biomolecular interactions using a governing equation that accounts for the participation of bulk water in the equilibria. In the first example, the binding affinities of two DNA duplexes, one of nine and one of 10 base pairs in length, are measured and characterized by isothermal titration calorimetry (ITC) as a function of concentration. The results indicate that the change in solvation free energy that accompanies duplex formation (ΔGS) is large and unfavorable. The duplex with the larger number of G:C pairings yields the largest change in solvation free energy, ΔGS = +460 kcal·mol−1per base pair at 25 °C. A van't Hoff analysis of the data is complicated by the varying degree of intramolecular base stacking within each DNA strand as a function of temperature. A modeling study reveals how the solvation free energy alters the output of a typical ITC experiment and leads to a good, though misleading, fit to the classical equilibrium equation. The same thermodynamic framework is applied to a model protein–ligand interaction, the binding of ribonuclease A with the nucleotide inhibitor 3′‐UMP, and to a conformational equilibrium, the change in tertiary structure of α‐lactalbumin in molar guanidinium chloride solutions. The ribonuclease study yields a value of ΔGS = +160 kcal·mol−1, whereas the folding equilibrium yields ΔGS ≈ 0, an apparent characteristic of hydrophobic interactions. These examples provide insight on the role of solvation energy in binding equilibria and suggest a pivot in the fundamental application of thermodynamics to solution chemistry.

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Quantifying Interactions and Solvent Effects Using Molecular Balances and Model Complexes

Cited by 35 publications

References 79 publications

Dissecting Solvent Effects on Hydrogen Bonding

Dissecting Solvent Effects on Hydrogen Bonding

Assessing the persistence of chalcogen bonds in solution with neural network potentials

Solvation free energy in governing equations for DNA hybridization, protein–ligand binding, and protein folding

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