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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Learning the relationship between nanoscale chemical patterning and hydrophobicity
The hydrophobicity of proteins and similar surfaces, which display chemical heterogeneity at the nanoscale, drives countless aqueous interactions and assemblies. However, predicting how surface chemical patterning influences hydrophobicity remains a challenge. Here, we address this challenge by using molecular simulations and machine learning to characterize and model the hydrophobicity of a diverse library of patterned surfaces, spanning a wide range of sizes, shapes, and chemical compositions. We find that simple models, based only on polar content, are inaccurate, whereas complex neural network models are accurate but challenging to interpret. However, by systematically incorporating chemical correlations between surface groups into our models, we are able to construct a series of minimal models of hydrophobicity, which are both accurate and interpretable. Our models highlight that the number of proximal polar groups is a key determinant of hydrophobicity and that polar neighbors enhance hydrophobicity. Although our minimal models are trained on particular patch size and shape, their interpretability enables us to generalize them to rectangular patches of all shapes and sizes. We also demonstrate how our models can be used to predict hot-spot locations with the largest marginal contributions to hydrophobicity and to design chemical patterns that have a fixed polar content but vary widely in their hydrophobicity. Our data-driven models and the principles they furnish for modulating hydrophobicity could facilitate the design of novel materials and engineered proteins with stronger interactions or enhanced solubilities.
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- NSF-PAR ID:
- 10382859
- Date Published:
- Journal Name:
- Proceedings of the National Academy of Sciences
- Volume:
- 119
- Issue:
- 48
- ISSN:
- 0027-8424
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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Performance of membranes for water purification is highly influenced by the interactions of solvated species with membrane surfaces, including surface adsorption of solutes upon fouling. Current efforts toward fouling-resistant membranes often pursue surface hydrophilization, frequently motivated by macroscopic measures of hydrophilicity, because hydrophobicity is thought to increase solute–surface affinity. While this heuristic has driven diverse membrane functionalization strategies, here we build on advances in the theory of hydrophobicity to critically examine the relevance of macroscopic characterizations of solute–surface affinity. Specifically, we use molecular simulations to quantify the affinities to model hydroxyl- and methyl-functionalized surfaces of small, chemically diverse, charge-neutral solutes represented in produced water. We show that surface affinities correlate poorly with two conventional measures of solute hydrophobicity, gas-phase water solubility and oil–water partitioning. Moreover, we find that all solutes show attraction to the hydrophobic surface and most to the hydrophilic one, in contrast to macroscopically based hydrophobicity heuristics. We explain these results by decomposing affinities into direct solute interaction energies (which dominate on hydroxyl surfaces) and water restructuring penalties (which dominate on methyl surfaces). Finally, we use an inverse design algorithm to show how heterogeneous surfaces, with multiple functional groups, can be patterned to manipulate solute affinity and selectivity. These findings, importantly based on a range of solute and surface chemistries, illustrate that conventional macroscopic hydrophobicity metrics can fail to predict solute–surface affinity, and that molecular-scale surface chemical patterning significantly influences affinity—suggesting design opportunities for water purification membranes and other engineered interfaces involving aqueous solute–surface interactions.
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Intracellular compartmentalization plays a pivotal role in cellular function, with membrane-bound organelles and membrane-less biomolecular 'condensates' playing key roles. These condensates, formed through liquid-liquid phase separation (LLPS), enable selective compartmentalization without the barrier of a lipid bilayer, thereby facilitating rapid formation/dissolution in response to stimuli. Intrinsically disordered proteins (IDPs) and/or proteins with intrinsically disordered regions (IDRs), which are often rich in charged and polar amino acid sequences, scaffold many condensates, often in conjunction with RNA. Comprehending the impact of IDP/IDR sequences on phase separation poses a challenge due to the extensive chemical diversity resulting from the myriad amino acids and post-translational modifications. To tackle this hurdle, one approach has been to investigate LLPS in simplified polypeptide systems, which offer a narrower scope within the chemical space for exploration. This strategy is supported by studies that have demonstrated how IDP function can largely be understood based on general chemical features, such as clusters or patterns of charged amino acids, rather than residue-level effects, and the ways in which these kinds of motifs give rise to an ensemble of conformations. Our lab has utilized complex coacervates assembled from oppositely-charged polypeptides as a simplified material analogue to the complexity of liquid-liquid phase separated biological condensates. Complex coacervation is an associative LLPS that occurs due to the electrostatic complexation of oppositely-charged macro-ions. This process is believed to be driven by the entropic gains resulting from the release of bound counterions and the reorganization of water upon complex formation. Apart from their direct applicability to IDPs, polypeptides also serve as excellent model polymers for investigating molecular interactions due to the wide range of available side-chain functionalities and the capacity to finely regulate their sequence, thus enabling precise control over interactions with guest molecules. Here, we discuss fundamental studies examining how charge patterning, hydrophobicity, chirality, and architecture affect the phase separation of polypeptide-based complex coacervates. These efforts have leveraged a combination of experimental and computational approaches that provide insight into the molecular level interactions. We also examine how these parameters affect the ability of complex coacervates to incorporate globular proteins and viruses. These efforts couple directly with our fundamental studies into coacervate formation, as such ‘guest’ molecules should not be considered as experiencing simple encapsulation and are instead active participants in the electrostatic assembly of coacervate materials. Interestingly, we observed trends in the incorporation of proteins and viruses into coacervates formed using different chain length polypeptides that are not well explained by simple electrostatic arguments and may be the result of more complex interactions between globular and polymeric species. Additionally, we describe experimental evidence supporting the potential for complex coacervates to improve the thermal stability of embedded biomolecules such as viral vaccines. Ultimately, peptide-based coacervates have the potential to help unravel the physics behind biological condensates while paving the way for innovative methods in compartmentalization, purification, and biomolecule stabilization. These advancements could have implications spanning from medicine to biocatalysis.more » « less
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Hydrophobic interactions play a central role in bioinspired strategies for molecular self-assembly in water, yet how these interactions are encoded by chemically heterogeneous interfaces is poorly understood. We report an experimental investigation of the influence of immobilized polar groups (amine) and cations (ammonium and guanidinium) on enthalpic and entropic contributions to hydrophobic interactions mediated by methyl-terminated surfaces at temperatures ranging from 298 K to 328 K and pH values between 3.5 to 10.5. We use our measurements to calculate the change in free energy (and enthalpic and entropic components) that accompanies transfer of each surface from aqueous TEA containing 60 vol% methanol into aqueous TEA ( i.e. , transfer free energy that characterizes hydrophobicity). We find the thermodynamic signature of the pure methyl surface (positive transfer enthalpy and entropy) to be altered qualitatively by incorporation of amine or guanidinium groups into the surface (negative transfer enthalpy and near zero transfer entropy). In contrast, ammonium groups immobilized on a methyl surface do not change the thermodynamic signature of the hydrophobic interaction. Compensation of entropy and enthalpy is clearly evident in our results, but the overall trends in the transfer free energies are dominated by enthalpic effects. This observation and others lead us to hypothesize that the dominant effect of the immobilized charged or polar groups in our experiments is to influence the number or strength of hydrogen bonds formed by interfacial water molecules adjacent to the nonpolar domains. Overall, these results provide insight into entropy–enthalpy compensation at chemically heterogeneous surfaces, and generate hypotheses and a rich experimental dataset for further exploration via simulation.more » « less
- Free Publicly Accessible Full Text
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Accepted Manuscript1.0
- Journal Article:
- https://doi.org/10.1073/pnas.2200018119
