Water-water Interactions Research Articles

Molecular Fingerprints of Hydrophobicity at Aqueous Interfaces from Theory and Vibrational Spectroscopies

Hydrophobicity/hydrophilicity of aqueous interfaces at the molecular level results from a subtle balance in the water–water and water–surface interactions. This is characterized here via density functional theory–molecular dynamics (DFT-MD) coupled with vibrational sum frequency generation (SFG) and THz-IR absorption spectroscopies. We show that water at the interface with a series of weakly interacting materials is organized into a two-dimensional hydrogen-bonded network (2D-HB-network), which is also found above some macroscopically hydrophilic silica and alumina surfaces. These results are rationalized through a descriptor that measures the number of “vertical” and “horizontal” hydrogen bonds formed by interfacial water, quantifying the competition between water–surface and water–water interactions. The 2D-HB-network is directly revealed by THz-IR absorption spectroscopy, while the competition of water–water and water–surface interactions is quantified from SFG markers. The combination of SFG and THz-IR spectroscopies is thus found to be a compelling tool to characterize the finest details of molecular hydrophobicity at aqueous interfaces.

Solvatochromism and Theoretical Studies of Dicyanobis(phenylpyridine)iridium(III) Complex Using Density Functional Theory

Luminescent cyanometallate [Ir(ppy)2(CN)2]– (ppy = C6H5C5H4N) has recently gained attention due to its desired photophysical properties. Our research group reported that the [Ir(ppy)2(CN)2]– has shown a negative solvatochromism like [Ru(bipy)(CN)4]2–, resulting in a blue-shift of the UV-Vis absorption bands in the water. Therefore, to gain insight into the specific solvent-solute interaction governed by the hydrogen bond in the solvation hydration shell, density functional theory (DFT) calculations were performed on the singlet ground state of the [Ir(ppy)2(CN)2]– and its solvent environment in the water at B3LYP level theory. It was demonstrated, seven water molecules provided a good description of the relevant spectra: IR and UV-Vis. The calculation reproduced the positions and intensities of the observed n(CºN) bands at 2069 and 2089 cm–1. The calculated MLCT transition wavelength was 366 nm vs. a measured value of 358 nm, differing by 8 nm. The study revealed the water molecules interacted with cyanide ligands through CN⋯H-OH type hydrogen bonds and water-water interactions (HO-H⋯OH2 type hydrogen bonds) were involved in the solvation hydration shell around the [Ir(ppy)2(CN)2]–.

The Many-Body Expansion for Aqueous Systems Revisited: II. Alkali Metal and Halide Ion-Water Interactions.

We present a detailed study of the many-body expansion (MBE) for alkali metal and halide ion-water interactions and quantify the effect of these ions on the strength of the surrounding aqueous hydrogen bonding environment. Building on our previous work on neutral water clusters [J. P. Heindel and S. S. Xantheas, J. Chem. Theor. Comput. 16 (11), 6843-6855 (2020)], we carry out the MBE for the alkali metal and halide ion-water clusters, Z+/-(H2O)9, where Z = Li+, Na+, K+, Rb+, Cs+, F-, Cl-, Br-, and I- and compare them with the results for a pure water cluster with the same number of "bodies", viz., (H2O)10. The 2-B ion-water (I-W) interaction accounts for a larger percentage of the total cluster binding energy compared to a pure water cluster of the same size, with the total 3-B term being smaller and of opposite sign (repulsive), whereas higher order terms are essentially negligible. The same oscillating behavior around zero for the MBE terms higher than the 5-B with a basis set that was reported for water clusters is also observed for the ion-water clusters considered here, with the basis set superposition error (BSSE) corrections amending this as in the water cluster case. A remarkable, linear anticorrelation between the total 2-B (I-W), the total 2-B (W-W), and also the 3-B (W-W-W) interactions is found, quantifying the effect of the different ions in disrupting and altering (weakening) the neighboring hydrogen bonded water network: stronger (I-W) interactions result in weaker (W-W) interactions. Additional linear correlations across the two series of alkali metals and halide ions were found between the 3-B (I-W-W) and the 2-B (I-W) as well as between the 3-B (I-W-W) and the 3-B (W-W-W) interactions, suggesting the existence of previously unrealized underlying physics governing these 2-B intermolecular and 3-B collective interactions. Our results further suggest a universal behavior of the two different families of ions (alkali metals and halides) for both the correlations of the various components of the total binding energies and the estimate of the 2-B BSSE correction, which is reported to follow a common profile for ion-water and water-water interactions when cast in terms of reduced distances and energies of the respective dimers. We expect the current results that quantify the interplay between ion-water and water-water interactions in aqueous clusters to impact the development of classical, ab initio-based force fields for monatomic ion solvation, whereas the insights into the nature of the BSSE to be critical in future ab initio-based, many-body molecular dynamics studies.

Nanoscale friction and adhesion mechanisms in articular cartilage top layer hydrated interfaces: Insights from atomistic simulations

This study investigates nanoscale adhesion and frictional behavior of an idealized cartilage-cartilage top layer atomistic contact model with nanoconfined water at the interface under range of load using three dimensional molecular dynamics (MD) simulations. Analysis reveals that water significantly replaces the cohesive interactions with adhesive at regions of unhydrated cartilage-cartilage contact by engulfing water molecules. These water molecules improve the load-bearing capacity and reduces frictional forces at the interface. Interfacial water also inhibits debonding at the interface during pull-off test at higher loads. Sliding tests reveal that at higher load-induced confined geometries there is a significant reduction in the frictional forces up to five times in comparison to dry collagen-collagen contact. Interaction energy curves predict that water molecules completely wet the collagen and thus provide an in-situ interfacial lubrication. Finally, the intermolecular interactions unveil the presence of substantial amount of water molecules at the interfaces to reduce friction drastically at the interface employing water-water interactions. Overall, a hydrated atomistic model for top layer cartilage-cartilage lubricated contact is developed and studied for adhesion and friction behavior and underlying mechanisms which is useful for understanding in-vivo boundary lubricated interfaces and design enhanced implant solutions.

Uncovering a Universal Molecular Mechanism of Salt Ion Adsorption at Solid/Water Interfaces.

Solid/water interfaces, in which salt ions come in close proximity to solids, are ubiquitous in nature. Because water is a polar solvent and salt ions are charged, a long-standing puzzle involving solid/water interfaces is how do the electric fields exerted by the salt ions and the interfacial water molecules polarize the charge distribution in the solid and how does this polarization, in turn, influence ion adsorption at any solid/water interface. Here, using state-of-the-art polarizable force fields derived from quantum chemical simulations, we perform all-atomistic molecular dynamics simulations to investigate the adsorption of various ions comprising the well-known Hofmeister series at the graphene/water interface, including comparing with available experimental data. Our findings reveal that, in vacuum, the ionic electric field-induced polarization of graphene results in a significantly large graphene-ion polarization energy, which drives all salt ions to adsorb to graphene. On the contrary, in the presence of water molecules, we show that the ions and the water molecules exert waves of molecular electric fields on graphene which destructively interfere with each other. This remarkable phenomenon is shown to cause a water-mediated screening of more than 85% of the graphene-ion polarization energy. Finally, by investigating superhydrophilic and superhydrophobic model surfaces, we demonstrate that this phenomenon occurs universally at all solid/water interfaces and results in a significant weakening of the ion-solid interactions, such that ion specific effects are governed primarily by a competition between the ion-water and water-water interactions, irrespective of the nature of the solid/water interface.

Salt Effects on the Structure and Dynamics of Interfacial Water on Calcite Probed by Equilibrium Molecular Dynamics Simulations

It is important to understand the properties of interfacial water at mineral surfaces. Since calcite is one of the most common minerals found in rocks and sedimentary deposits, and since it represents a likely phase encountered in reservoirs dedicated to carbon sequestration, it is crucial to understand the behaviour of fluids on its surface. In this study, the impacts of sodium chloride (NaCl), potassium chloride (KCl) and magnesium chloride (MgCl2) on the structure and dynamics of water on the calcite interface were investigated using equilibrium molecular dynamics simulations. Two force fields were compared to model calcite. The resultant properties of interfacial water were quantified and compared in terms of atomic density profiles, surface density distributions, radial distribution functions, hydrogen bond density profiles, angular distributions, and residence times. Our results show the formation of distinct interfacial molecular layers, with water molecules in each layer having slightly different orientations, depending on the force field implemented. The fluid behaviour within the first interfacial layers differs from that observed in bulk water. There was a tendency for water molecules in adjacent layers to form hydrogen bonds between each other or the surface, as opposed to the formation of hydrogen bonds within each hydration layer. The addition of ions disrupts the well-organized structure of oxygen atoms in the first and second hydration layers, with KCl having the biggest effect. Conversely, far from the interface, MgCl2 leads to the lowest number of hydrogen bonds per water, out of the salts considered. The residence time of water within the second hydration layer follows a bi-exponential decay, suggesting the simultaneous presence of two dynamic mechanisms, one characterized by shorter time scales than the other. The time scale associated with the former mechanism decreases as the salt concentration is increased, whereas the opposite is observed for the slower mechanism. In general, the results obtained with the two force fields used to simulate calcite are similar in terms of the features of the hydration layers and hydrogen bond network but differ significantly in their predictions for the residence times. Although experimental results are not available to identify which of the two force fields yields predictions that more closely resemble reality, the results highlight the contributions of surface-water, water-water, and ion-water interactions on the wetting properties of calcite, which are especially important for calcite-water-electrolyte interactions commonly observed in nature.

Osmosis-Driven Water Transport through a Nanochannel: A Molecular Dynamics Simulation Study

In this work, we study a chemical method to transfer water molecules from a nanoscale compartment to another initially empty compartment through a nanochannel. Without any external force, water molecules do not spontaneously move to the empty compartment because of the energy barrier for breaking water hydrogen bonds in the transport process and the attraction between water molecules and the compartment walls. To overcome the energy barrier, we put osmolytes into the empty compartment, and to remove the attraction, we weaken the compartment-water interaction. This allows water molecules to spontaneously move to the empty compartment. We find that the initiation and time-transient behavior of water transport depend on the properties of the osmolytes specified by their number and the strength of their interaction with water. Interestingly, when osmolytes strongly interact with water molecules, transport immediately starts and continues until all water molecules are transferred to the initially empty compartment. However, when the osmolyte interaction strength is intermediate, transport initiates stochastically, depending on the number of osmolytes. Surprisingly, because of strong water-water interactions, osmosis-driven water transport through a nanochannel is similar to pulling a string at a constant speed. Our study helps us understand what minimal conditions are needed for complete transfer of water molecules to another compartment through a nanochannel, which may be of general concern in many fields involving molecular transfer.

The Many-Body Expansion for Aqueous Systems Revisited: I. Water-Water Interactions.

We revisit the many-body expansion (MBE) for water-water interactions by examining the effects of the basis set, including those resulting from the basis set superposition error (BSSE) correction, and electron correlation on the various terms for selected sizes of water clusters up to n = 21. The analysis is performed at the second-order Møller-Plesset (MP2) perturbation theory with the family of augmented correlation consistent basis sets up to five zeta quality (aug-cc-pVxZ, x = D, T, Q, 5) for the (H2O)n, n = 7, 10, 13, 16, and 21, clusters for which we report either the complete MBE (for n = 7, 10) or the ones through the 6-body (for n = 13) and the 5-body terms (for n = 16, 21). For the n = 3 and 7 clusters, we also report the analysis at the coupled cluster with single, double, and perturbative triple replacements in order to assess the effects of a higher correlation on the magnitude and percentage of the various MBE terms. Our results suggest that the oscillatory behavior around zero found for the 5-body and larger terms is solely an artifact of the (small) size of the basis set. Indeed, all terms above the 4-body converge monotonically to practically zero upon increasing the size of the basis set toward the complete basis set (CBS) limit. In that respect, the BSSE-corrected 5-body and above terms do not exhibit the oscillatory behavior on either side of zero with the basis set observed for the BSSE-uncorrected terms. In addition, the magnitudes of the 5-body and above terms are accurately reproduced even with the smaller basis set of the series (aug-cc-pVDZ) once the BSSE correction is taken into account. The same level of theory (MP2/aug-cc-pVDZ, BSSE-corrected) also accurately reproduces the MP2/CBS values of the 3- and 4-body terms. The contribution of electron correlation to the 3- and 4-body terms is quite small so that neglecting the correlation contribution in all terms above the 3-body results in an error of the order of 0.1%. The BSSE correction to the largest 2-body term in the MBE was accurately estimated from the function a[1 + erf( - b·R)], which is proportional to the common (overlapping) area between two Gaussian distributions whose centers are separated by R with the constants a and b fitted to the calculated BSSE corrections for the individual 2-body terms of the clusters with each basis set and R is the distance between oxygen atoms. Our results demonstrate that the MBE for water-water interactions converges by the 4-body term since any finite terms above the 4-body are artifacts of the size of the basis set. The MBE can thus be safely truncated at the 4-body term when either a very large basis set is used or BSSE corrections are taken into account even with the smaller aug-cc-pVDZ basis set. We expect these findings to have important consequences in the pursuit of accurate ab initio based many-body molecular dynamics simulations for aqueous systems.

Microsolvation of Co- in water: Density functional theory calculations coupled with stochastic kicking method.

The hydrated clusters [Formula: see text] (n = 1-4) in gas phase are studied by density functional theory calculations (DFT) coupled with stochastic kicking method. The global minimum structure of [Formula: see text] exhibits low-symmetry pattern since only one H atom of water molecules interact with Co- ion and other ones associate with a network of hydrogen bonds. The Co- ion prefers to locate at vertex site of the water molecular clusters in such way to reduce the repulsion with O atom. These results elucidate the formation of these low-lying isomers are determined by the delicate balance between ion-water and water-water interactions.

Water structure and hydration of polymer network in PMEO2MA hydrogels

The hydration of amphiphilic polymers with some different hydrophilic centers, such as poly(2-(2-methoxyethoxy)ethyl methacrylate) (PMEO2MA), is important to understand well their thermo-responsivity. The PMEO2MA hydrogels with varying swelling degree, synthetized by radiation-induced cross-linking polymerization, has been investigated by ATR-FTIR supported by DFT calculations. This study broadens the knowledge about mechanism of hydration of PMEO2MA and explores the relationships between the water content in hydrogels, polymer-water, and water-water interactions. A complete picture of hydration processes of all hydrophilic centers (carbonyl and ether groups) was shown and correlated with water structure for the first time. It was found that firstly, small water clusters, and water bridges between the polymer segments are formed. Next, the bridges break and polymer chains start to separate. Finally, water tend to structure characteristic for bulk water. The obtained results may be an excellent basis for the analysis of local changes in PMEO2MA hydration during volume phase transition.

Competitive adsorption of benzene and water vapor on lignite-based activated carbon: Experiment and molecular simulation study

Exploring the effect of water vapor on the benzene adsorptive behavior is of practical importance and scientific interest. The presence of water vapor in the gas stream altered the breakthrough curves of benzene, as well as the selectivity of carbon materials towards adsorbates. The work herein elucidated the competitive adsorption mechanism based on experimental observation and molecular simulation. At relative humidity (RH) 10%, water molecules showed less effect on the benzene adsorption that benzene entered the micropores and mesopores while water molecules were primarily adsorbed in the mesopores. Since the polar water molecules presented higher affinity towards the surface functionalities, these molecules preferentially occupied the adsorption site via hydrogen bonding with increased RH. Water cluster was gradually formed through water-water interactions which were characteristics of pore filling. A two-layer stacking of adsorbates was observed for co-adsorption. The first layer was primarily composed of water molecules with the average distance of 2.99 ~ 3.19 Å to the surface functionalities. The second layer was primarily benzene molecules which were aggregated in T-shaped, displaced T-shaped and parallel configurations. These molecules were separated at 4.67 ~ 6.17 Å from the functional groups, and mainly adsorbed by water-benzene interaction (via hydrogen bonding).

Conductance and Configuration of Molecular Gold-Water-Gold Junctions under Electric Fields

Water molecules can mediate charge transfer in biological and chemical reactions by forming electronic coupling pathways. Understanding the mechanism requires a molecular-level electrical characterization of water. Here, we describe the measurement of single water molecular conductance at room temperature, characterize the structure of water molecules using infrared spectroscopy, and perform theoretical studies to assist in the interpretation of the experimental data. The study reveals two distinct states of water, corresponding to a parallel and perpendicular orientation of the molecules. Water molecules switch from parallel to perpendicular orientations on applying an electric field, producing switching from high to low conductance states, thus enabling the determination of single water molecular dipole moments. The work further shows that water-water interactions affect the atomic scale configuration and conductance of water molecules. These findings demonstrate the importance of the discrete nature of water molecules in electron transfer and set limits on water-mediated electron transfer rates.

Infrared photodissociation spectroscopy of D2-tagged CH3CO2 −(H2O)0−2 anions

ABSTRACT Infrared photodissociation spectroscopy of D2-tagged anions is used to obtain the vibrational spectra of microsolvated acetate, (n = 0–2), in the CH/OH stretching (∼4000–2500 cm−1) and fingerprint (∼1800–800 cm−1) spectral regions. These results are analysed by comparison to anharmonic IR spectra from MP2 calculations as well as Born-Oppenheimer molecular dynamics (BOMD) simulations. In agreement with prior work, we find that the first water molecule adds to the acetate anion by donating two hydrogen bonds, yielding a symmetrical structure involving a six-membered hydrogen-bonded ring. Two nearly degenerate binding motifs that differ in energy by less than 1 kJ/mol are identified for n = 2 anion, where the lowest-energy geometry has two ion-water hydrogen bonds as well as a water-water hydrogen bond. The molecular dynamics simulations confirm that this lower-energy structure is preferred over a slightly higher-lying configuration possessing three ion-water hydrogen bonds and no water-water interactions. Analysis of the molecular motion contributing to peaks in the BOMD spectra via a generalised normal mode approach provides assignment of all observed transitions to the lower-energy structure, and enables distinction of the vibrational signatures associated with ion-water and water-water intermolecular motions.

Hydration and dehydration of water of bentonite: A solid-state 1H magic-angle spinning NMR study

Molecular-level interactions of interlayer water near the montmorillonite surfaces were investigated on commercial bentonite using solid-state 1H magic-angle spinning NMR spectroscopy. It was observed that when the water content was higher than about 3 wt%, the chemical shift of samples increases as the increase in water content, while it decreases when the water content was lower than about 3 wt% with the increase of water content. Dehydration experiments at low water content and theoretical calculation showed that there might be two types of interaction in the interlayer space of montmorillonite: the water-water interaction and cation-water interaction. Water-water interaction was dominant at relatively high water content and cation-water interaction was dominant at relatively low water contents. The water-water interaction formed loosely bound water and the water-cation interaction formed tightly bound water near the montmorillonite surfaces.

Ions Tune Interfacial Water Structure and Modulate Hydrophobic Interactions at Silica Surfaces.

The structure and ultrafast dynamics of the electric double layer (EDL) are central to chemical reactivity and physical properties at solid/aqueous interfaces. While the Gouy-Chapman-Stern model is widely used to describe EDLs, it is solely based on the macroscopic electrostatic attraction of electrolytes for the charged surfaces. Structure and dynamics in the Stern layer are, however, more complex because of competing effects due to the localized surface charge distribution, surface-solvent-ion correlations, and the interfacial hydrogen bonding environment. Here, we report combined time-resolved vibrational sum frequency generation (TR-vSFG) spectroscopy with ab initio DFT-based molecular dynamics simulations (AIMD/DFT-MD) to get direct access to the molecular-level understanding of how ions change the structure and dynamics of the EDL. We show that innersphere adsorbed ions tune the hydrophobicity of the silica-aqueous interface by shifting the structural makeup in the Stern layer from dominant water-surface interactions to water-water interactions. This drives an initially inhomogeneous interfacial water coordination landscape observed at the neat interface toward a homogeneous, highly interconnected in-plane 2D hydrogen bonding (2D-HB) network at the ionic interface, reminiscent of the canonical, hydrophobic air-water interface. This ion-induced transformation results in a characteristic decrease of the vibrational lifetime (T1) of excited interfacial O-H stretching modes from T1 ∼ 600 fs to T1 ∼ 250 fs. Hence, we propose that the T1 determined by TR-vSFG in combination with DFT-MD simulations can be widely used for a quantitative spectroscopic probe of the ion kosmotropic/chaotropic effect at aqueous interfaces as well as of the ion-induced surface hydrophobicity.

Water confined (H2O) n=1–10 amino acid-based ionic liquids – A DFT study on the bonding, energetics and IR spectra

Abstract Effect of water confinement on the structural properties, energetics, and spectral signatures of amino acid-based ionic liquids (AAILs) is a subject of scientific importance. We have confined AAILs using the water molecules in the form of clusters with size varying from n = 1 to 10. Hydrogen bonds characterize the orientation of water clusters on AAILs. Water molecules predominantly interact via strong electrostatic O-H⋯X (N, O) interactions with anions and form comparatively weaker C-H⋯O bonds with cations. A minimum of n = 3 water molecules is needed to initiate the dilution of AAIL, irrespective of the anion species. The increase in the water molecules beyond n = 3 occupies the interstitial space between anion and cation, weakening the anion-cation interactions. The sequential addition of water molecules in the system shows the cooperative interaction between cation-anion, anion-water, cation-water, and water-water units. However, until n = 3, anion-water interaction is predominant, beyond which water-water interaction gains strength progressively. Aliphatic AAILs exhibit stronger hydrogen bonding interaction than aromatic ILs.

Mechanism of surface hydration of potassium carbonate: Insights from first-principles simulations

In this work, the density functional theory simulations were performed to analyze the hydration mechanism of single and multiple water molecules over K2CO3(0 0 1) surface. A single water molecule preferentially adsorbed on the hollow site through a hydrogen bond and an ionic bond. Mulliken charge analysis showed that electrons were transferred from the potassium atom on K2CO3(0 0 1) surface to the H2O molecule. To investigate the impact of water molecule coverage, the configurations of multiple water molecules adsorbed on K2CO3(0 0 1) surface at different coverages (from 0.5 to 1.5 monolayers) were optimized. The results indicated that one monolayer of water molecules adsorbed on K2CO3(0 0 1) surface is the most stable configuration because of well water-water and water-surface interactions, where four water molecules generate a head-to-tail water chain by hydrogen bonding. Interestingly, the distances between the adjacent molecule layers increased with increasing water coverage, suggesting that the potassium carbonate expands during the earlier hydration process. In addition, the geometric parameters of the hydrogen bonds were obtained and we found that the hydrogen bonds formed by the combination of water molecules on substrate obeyed the bond valence model.

Sampling Solvation Free Energy of Electrolytic Solvents with 3D2PT

Interactions between biomolecules and their surrounding solvation environment contribute significantly to their stability and to the driving forces for complex formation and conformational change. However, exploring the impact of solvation on these processes requires a thorough quantification of thermodynamic contributions to changes in the free energy of the system. Microscopic details available in atomistic molecular dynamics simulations allow for the extraction of solvation enthalpies from pair-wise additive protein-water and water-water interactions relative to the bulk solvent. The 3D-2PT method developed in the Heyden lab at Arizona State University complements this information with an analysis of hydration water entropies obtained from an analysis of intermolecular vibrations. Both the solvation enthalpy and entropy are analyzed on three-dimensional grids with 0.5-1.0 Å resolution allowing for direct thermodynamic insights into local hydration sites at the protein-water interface.Here, the original 3D-2PT approach is expanded to include contributions of electrolytes to the solvation enthalpy, entropy and free energy. This is achieved in a mixed resolution approach, which considers the drastic differences in concentration between water (∼55 M) and electrolytes (∼0.15 M) and resulting statistics for local environments. In addition to an analysis of water and ion vibrations in their local coordination environments, the new analysis distinguishes solute-water, solute-ion, water-water, ion-ion and water-ion interactions and their contributions to the solvation enthalpy.

An equation for the isosbestic point wavelength in aqueous solutions of electrolytes

The existence of an isosbestic point in the OH bond vibration band of H2O molecules in solutions of strong electrolytes has been shown by many research groups but its physical meaning has been only recently read as the equilibrium point between two populations of water molecules where either water-ion or water-water interactions respectively prevail. Thus the isosbestic point provides useful information on the bulk displacement of water molecules in presence of solutes. Herein we show that the isosbestic point occurrence is correctly described by an equation describing the balance of the electrostatic forces. Furthermore, its wavelength is also related to the slope of the density vs. the solute concentration. These results support the view that the effect of the solute can be barely regulated within few hydration shells.

Water in protein hydration and ligand recognition.

This review describes selected basics of water in biomolecular recognition. We focus on a qualitative understanding of the most important physical aspects, how these change in magnitude between bulk water and protein environment, and how the roles that water plays for proteins arise from them. These roles include mechanical support, thermal coupling, dielectric screening, mass and charge transport, and the competition with a ligand for the occupation of a binding site. The presence or absence of water has ramifications that range from the thermodynamic binding signature of a single ligand up to cellular survival. The large inhomogeneity in water density, polarity and mobility around a solute is hard to assess in experiment. This is a source of many difficulties in the solvation of protein models and computational studies that attempt to elucidate or predict ligand recognition. The influence of water in a protein binding site on the experimental enthalpic and entropic signature of ligand binding is still a point of much debate. The strong water‐water interaction in enthalpic terms is counteracted by a water molecule's high mobility in entropic terms. The complete arrest of a water molecule's mobility sets a limit on the entropic contribution of a water displacement process, while the solvent environment sets limits on ligand reactivity.