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1. Quantitative entropy–enthalpy compensation in intraprotein interactions from model compound data

   https://doi.org/10.1002/pro.5013  

   Redvanly, Thomas W; Pielak, Gary J (June 2024, Protein Science)

   Abstract Many small globular proteins exist in only two states—the physiologically relevant folded state and an inactive unfolded state. The active state is stabilized by numerous weak attractive contacts, including hydrogen bonds, other polar interactions, and the hydrophobic effect. Knowledge of these interactions is key to understanding the fundamental equilibrium thermodynamics of protein folding and stability. We focus on one such interaction, that between amide and aromatic groups. We provide a statistically convincing case for quantitative, linear entropy–enthalpy compensation in forming aromatic–amide interactions using published model compound transfer‐free energy data. 

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2. Structural features of interfacial water predict the hydrophobicity of chemically heterogeneous surfaces

   https://doi.org/10.1039/d2sc02856e  

   Dallin, Bradley C.; Kelkar, Atharva S.; Van Lehn, Reid C. (February 2023, Chemical Science)

   The hydrophobicity of an interface determines the magnitude of hydrophobic interactions that drive numerous biological and industrial processes. Chemically heterogeneous interfaces are abundant in these contexts; examples include the surfaces of proteins, functionalized nanomaterials, and polymeric materials. While the hydrophobicity of nonpolar solutes can be predicted and related to the structure of interfacial water molecules, predicting the hydrophobicity of chemically heterogeneous interfaces remains a challenge because of the complex, non-additive contributions to hydrophobicity that depend on the chemical identity and nanoscale spatial arrangements of polar and nonpolar groups. In this work, we utilize atomistic molecular dynamics simulations in conjunction with enhanced sampling and data-centric analysis techniques to quantitatively relate changes in interfacial water structure to the hydration free energy (a thermodynamically well-defined descriptor of hydrophobicity) of chemically heterogeneous interfaces. We analyze a large data set of 58 self-assembled monolayers (SAMs) composed of ligands with nonpolar and polar end groups of different chemical identity (amine, amide, and hydroxyl) in five mole fractions, two spatial patterns, and with scaled partial charges. We find that only five features of interfacial water structure are required to accurately predict hydration free energies. Examination of these features reveals mechanistic insights into the interfacial hydrogen bonding behaviors that distinguish different surface compositions and patterns. This analysis also identifies the probability of highly coordinated water structures as a unique signature of hydrophobicity. These insights provide a physical basis to understand the hydrophobicity of chemically heterogeneous interfaces and connect hydrophobicity to experimentally accessible perturbations of interfacial water structure. 

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3. Identifying nonadditive contributions to the hydrophobicity of chemically heterogeneous surfaces via dual-loop active learning

   https://doi.org/10.1063/5.0072385  

   Kelkar, Atharva S.; Dallin, Bradley C.; Van Lehn, Reid C. (January 2022, The Journal of chemical physics)

   Hydrophobic interactions drive numerous biological and synthetic processes. The materials used in these processes often possess chemically heterogeneous surfaces that are characterized by diverse chemical groups positioned in close proximity at the nanoscale; examples include functionalized nanomaterials and biomolecules like proteins and peptides. Nonadditive contributions to the hydrophobicity of such surfaces depend on the chemical identities and spatial patterns of polar and nonpolar groups in ways that remain poorly understood. Here, we develop a dual-loop active learning framework that combines a fast, reduced-accuracy method (a convolutional neural network) with a slow, higher-accuracy method (molecular dynamics simulations with enhanced sampling) to efficiently predict the hydration free energy, a thermodynamic descriptor of hydrophobicity, for nearly 200,000 chemically heterogeneous self-assembled monolayers (SAMs). Analysis of this data set reveals that SAMs with distinct polar groups exhibit substantial variations in hydrophobicity as a function of their composition and patterning, but the clustering of nonpolar groups is a common signature of highly hydrophobic patterns. Further MD analysis relates such clustering to the perturbation of interfacial water structure. These results provide new insight into the influence of chemical heterogeneity on hydrophobicity via quantitative analysis of a large set of surfaces, enabled by the active learning approach.  

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4. Thermodynamics of calcium binding to heparin: Implications of solvation and water structuring for polysaccharide biofunctions

   https://doi.org/10.1073/pnas.2504348122  

   Knight, Brenna M; Gallagher, Connor_M B; Schulz, Michael D; Edgar, Kevin J; McNaul, Caylyn D; McCutchin, Christina A; Dove, Patricia M (September 2025, Proceedings of the National Academy of Sciences)

   Heparan sulfates are found in all animal tissues and have essential roles in living systems. This family of biomacromolecules modulates binding to calcium ions (Ca²⁺) in low free energy reactions that influence biochemical processes from cell signaling and anticoagulant efficacy to biomineralization. Despite their ubiquity, the thermodynamic basis for how heparans and similarly functionalized biomolecules regulate Ca²⁺interactions is not yet established. Using heparosan (Control) and heparins with different positions of sulfate groups, we quantify how SO₃⁻and COO⁻content and SO₃⁻position modulate Ca²⁺binding by isothermal titration calorimetry. The free energy of all heparin-Ca²⁺interactions (ΔG_rxn) is dominated by entropic contributions due to favorable water release from polar, hydrophilic groups. Heparin with both sulfate esters (O-SO₃⁻) and sulfamides (N-SO₃⁻) has the strongest binding to Ca²⁺compared to heparosan and to heparin with onlyO-SO₃⁻groups (~3X). By linking Ca²⁺binding thermodynamics to measurements of the interfacial energy for calcite (CaCO₃) crystallization onto polysaccharides, we show molecule-specific differences in nucleation rate can be explained by differences in water structuring during Ca²⁺interactions. A large entropic term (-TΔS_rxn) upon Ca²⁺–polysaccharide binding correlates with high interfacial energy to CaCO₃nucleation. Combining our measurements with literature values indicates many Ca²⁺–polysaccharide interactions have a shared thermodynamic signature. The resulting enthalpy–entropy compensation relationship suggests these interactions are generally dominated by water restructuring involving few conformational changes, distinct from Ca²⁺–protein binding. Our findings quantify the thermodynamic origins of heparin-specific interactions with Ca²⁺and demonstrate the contributions of solvation and functional group position during biomacromolecule-mediated ion regulation. 

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5. Different temperature- and pressure-effects on the water-mediated interactions between hydrophobic, hydrophilic, and hydrophobic–hydrophilic nanoscale surfaces

   https://doi.org/10.1063/5.0097908  

   Engstler, Justin; Giovambattista, Nicolas (August 2022, The Journal of Chemical Physics)

   Water-mediated interactions (WMIs) are responsible for diverse processes in aqueous solutions, including protein folding and nanoparticle aggregation. WMI may be affected by changes in temperature and pressure, and hence, they can alter chemical/physical processes that occur in aqueous environments. Traditionally, attention has been focused on hydrophobic interactions while, in comparison, the role of hydrophilic and hybrid (hydrophobic–hydrophilic) interactions have been mostly overlooked. Here, we study the role of T and P on the WMI between nanoscale (i) hydrophobic–hydrophobic, (ii) hydrophilic–hydrophilic, and (iii) hydrophilic–hydrophobic pairs of (hydroxylated/non-hydroxylated) graphene-based surfaces. We find that hydrophobic, hydrophilic, and hybrid interactions are all sensitive to P. However, while hydrophobic interactions [case (i)] are considerably sensitive to T-variations, hydrophilic [case (ii)] and hybrid interactions [case (iii)] are practically T-independent. An analysis of the entropic and enthalpic contributions to the potential of mean force for cases (i)–(iii) is also presented. Our results are important in understanding T- and P-induced protein denaturation and the interactions of biomolecules in solution, including protein aggregation and phase separation processes. From the computational point of view, the results presented here are relevant in the design of implicit water models for the study of molecular and colloidal/nanoparticle systems at different thermodynamic conditions. 

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