The Stability of Cyclodextrin Complexes in Solution.

Starting from known properties of non-specific salt effects on the surface tension at an air–water interface, we propose the first general, detailed qualitative molecular mechanism for the origins of ion-specific (Hofmeister) effects on the surface potential difference at an air–water interface; this mechanism suggests a simple model for the behaviour of water at all interfaces (including water–solute interfaces), regardless of whether the non-aqueous component is neutral or charged, polar or non-polar Specifically, water near an isolated interface is conceptually divided into three layers, each layer being 1 water-molecule thick We propose that the solute determines the behaviour of the adjacent first interfacial water layer ( I 1 ); that the bulk solution determines the behaviour of the third interfacial water layer ( I 3 ), and that both I 1 and I 3 compete for hydrogen-bonding interactions with the intervening water layer ( I 2 ), which can be thought of as a transition layer The model requires that a polar kosmotrope (polar water-structure maker) interact with I 1 more strongly than would bulk water in its place; that a chaotrope (water-structure breaker) interact with I 1 somewhat less strongly than would bulk water in its place; and that a non-polar kosmotrope (non-polar water-structure maker) interact with I 1 much less strongly than would bulk water in its place We introduce two simple new postulates to describe the behaviour of I 1 water molecules in aqueous solution The first, the ‘relative competition’ postulate, states that an I 1 water molecule, in maximizing its free energy (—δG), will favour those of its highly directional polar (hydrogen-bonding) interactions with its immediate neighbours for which the maximum pairwise enthalpy of interaction (—δ H ) is greatest; that is, it will favour the strongest interactions We describe such behaviour as ‘compliant’, since an I 1 water molecule will continually adjust its position to maximize these strong interactions Its behaviour towards its remaining immediate neighbours, with whom it interacts relatively weakly (but still favourably), we describe as ‘recalcitrant’, since it will be unable to adjust its position to maximize simultaneously these interactions The second, the ‘charge transfer’ postulate, states that the strong polar kosmotrope–water interaction has at least a small amount of covalent character, resulting in significant transfer of charge from polar kosmotropes to water–especially of negative charge from Lewis bases (both neutral and anionic); and that the water-structuring effect of polar kosmotropes is caused not only by the tight binding (partial immobilization) of the immediately adjacent ( I 1 ) water molecules, but also by an attempt to distribute among several water molecules the charge transferred from the solute When extensive, cumulative charge transfer to solvent occurs, as with macromolecular polyphosphates, the solvation layer (the layer of solvent whose behaviour is determined by the solute) can become up to 5- or 6-water-molecules thick We then use the ‘relative competition’ postulate, which lends itself to simple diagramming, in conjunction with the ‘charge transfer’ postulate to provide a new, startlingly simple and direct qualitative explanation for the heat of dilution of neutral polar solutes and the temperature dependence of relative viscosity of neutral polar solutes in aqueous solution This explanation also requires the new and intriguing general conclusion that as the temperature of aqueous solutions is lowered towards o °C, solutes tend to acquire a non-uniform distribution in the solution, becoming increasingly likely to cluster 2 water molecules away from other solutes and surfaces (the driving force for this process being the conversion of transition layer water to bulk water) The implications of these conclusions for understanding the mechanism of action of general (gaseous) anaesthetics and other important interfacial phenomena are then addressed

https://www.cambridge.org/core/services/aop-cambridge-core/content/view/S0033583500005369

The Hofmeister effect and the behaviour of water at interfaces.

Molecular recognition in biological systems relies on the existence of specific attractive interactions between two partner molecules. Structure-based drug design seeks to identify and optimize such interactions between ligands and their host molecules, typically proteins, given their three-dimensional structures. This optimization process requires knowledge about interaction geometries and approximate affinity contributions of attractive interactions that can be gleaned from crystal structure and associated affinity data.

Here we compile and review the literature on molecular interactions as it pertains to medicinal chemistry through a combination of careful statistical analysis of the large body of publicly available X-ray structure data and experimental and theoretical studies of specific model systems. We attempt to extract key messages of practical value and complement references with our own searches of the CSDa,(1) and PDB databases.(2) The focus is on direct contacts between ligand and protein functional groups, and we restrict ourselves to those interactions that are most frequent in medicinal chemistry applications. Examples from supramolecular chemistry and quantum mechanical or molecular mechanics calculations are cited where they illustrate a specific point. The application of automated design processes is not covered nor is design of physicochemical properties of molecules such as permeability or solubility.

Throughout this article, we wish to raise the readers’ awareness that formulating rules for molecular interactions is only possible within certain boundaries. The combination of 3D structure analysis with binding free energies does not yield a complete understanding of the energetic contributions of individual interactions. The reasons for this are widely known but not always fully appreciated. While it would be desirable to associate observed interactions with energy terms, we have to accept that molecular interactions behave in a highly nonadditive fashion.3,4 The same interaction may be worth different amounts of free energy in different contexts, and it is very hard to find an objective frame of reference for an interaction, since any change of a molecular structure will have multiple effects. One can easily fall victim to confirmation bias, focusing on what one has observed before and building causal relationships on too few observations. In reality, the multiplicity of interactions present in a single protein−ligand complex is a compromise of attractive and repulsive interactions that is almost impossible to deconvolute. By focusing on observed interactions, one neglects a large part of the thermodynamic cycle represented by a binding free energy: solvation processes, long-range interactions, conformational changes. Also, crystal structure coordinates give misleadingly static views of interactions. In reality a macromolecular complex is not characterized by a single structure but by an ensemble of structures. Changes in the degrees of freedom of both partners during the binding event have a large impact on binding free energy.

The text is organized in the following way. The first section treats general aspects of molecular design: enthalpic and entropic components of binding free energy, flexibility, solvation, and the treatment of individual water molecules, as well as repulsive interactions. The second half of the article is devoted to specific types of interactions, beginning with hydrogen bonds, moving on to weaker polar interactions, and ending with lipophilic interactions between aliphatic and aromatic systems. We show many examples of structure−activity relationships; these are meant as helpful illustrations but individually can never confirm a rule.

http://pubs.acs.org/doi/pdf/10.1021/jm100112j

A Medicinal Chemist’s Guide to Molecular Interactions

This article presents evidence for the existence of a specific linear relationship between the entropy change and the enthalpy change in a variety of processes of small solutes in water solution. The processes include solvation of ions and nonelectrolytes, hydrolysis, oxidation–reduction, ionization of weak electrolytes, and quenching of indole fluorescence among others. The values of the proportionality constant, called the compensation temperature, lie in a relatively narrow range, from about 250 to 315 °K, for all these processes. Such behavior can be a consequence of experimental errors but for a number of the processes the precision of the data is sufficient to show that the enthalpy–entropy compensation pattern is real. It is tentatively concluded that the pattern is real, very common and a consequence of the properties of liquid water as a solvent regardless of the solutes and the solute processes studied. As such the phenomenon requires that theoretical treatments of solute processes in water be expanded by inclusion of a specific treatment of the characteristic of water responsible for compensation behavior. The possible bases of the effect are proposed to be temperature-independent heat-capacity changes and/or shifts in concentrations of the two phenomenologically significant species of water. The relationship of these alternatives to the two-state process of water suggested by spectroscopic and relaxation studies is examined. The existence of a similar and probably identical relationship between enthalpy and entropy change in a variety of protein reactions suggests that liquid water plays a direct role in many protein processes and may be a common participant in the physiological function of proteins. It is proposed that the linear enthalpy–entropy relationship be used as a diagnostic test for the participation of water in protein processes. On this basis the catalytic processes of chymotrypsin and acetylcholinesterase are dominated by the properties of bulk water. The binding of oxygen by hemoglobin may fall in the same category. Similarities and differences in the behavior of small-solute and protein processes are examined to show how they may be related. No positive conclusions are established, but it is possible that protein processes are coupled to water via expansions and contractions of the protein and that in general the special pattern of enthalpy–entropy compensation is a consequent of the properties of water which require that expansions and contractions of solutes effect changes in the free volume of the nearby liquid water. It is shown that proteins can be expected to respond to changes in nearby water and interfacial free energy by expansions and contractions. Such responses may explain a variety of currently unexplained characteristics of protein solutions. More generally, the enthalpy–entropy compensation pattern appears to be the thermodynamic manifestation of “structure making” and “structure breaking,” operationally defined terms much used in discussions of water solutions. If so, the compensation pattern is ubiquitous and requires re-examination of a large body of molecular interpretations derived from quantitative studies of processes in water. Theories of processes in water may have to be expanded to accommodate this aspect of water behavior.

Enthalpy-entropy compensation phenomena in water solutions of proteins and small molecules: a ubiquitous property of water.

Helicenes: synthesis and applications.

This progress report is concerned primarily with problems relating to the structure and reactions of hydroxamic acids and N-hydroxyimides, and also surveys some of the biological activities of these compounds. Particular significance attaches to the Lossen rearrangement of O-acylated hydroxamic acids, which leads to isocyanates or their reaction products.

The Chemistry of Hydroxamic Acids and N-Hydroxyimides

On the enthalpy-entropy-relationship

Additive physical properties. I. General relationships and problems of statistical nature

The practical usefulness of a correlation equation as well as its significance in theory strongly depend on its range of validity, not only as it is defined but also as its use is restricted in practice by the number of parameters actually known. Hence the tables of parameters are of primary importance and reflect the actual state of a given field. In this chapter attention is focused on constants characterizing the substituent, which are mainly denoted by the letter σ with various subscripts and superscripts, but sometimes also by other symbols (E s, v). The correlation equation most frequently has the form (10.1). For the most common equations of this type 

$$y = \rho _0 + \sum\limits_{i = 1}^A {\rho _i \sigma _i } $$

(10.1)

(Hammett, Taft, Yukawa-Tsuno) many tabulations of σ constants are available (e.g. Refs. 1–13), but authors usually select from the literature only one preferred value for each substituent and the extent of the table is always a compromise between two demands: reliability and completeness. Actually neither can be fully satisfied, so that the user cannot really rely on all the data on the one hand, and must always search for additional data on the other. The problem is more urgent than with the tabulation of any other constants, since the individual σ values are not only of varying precision but may even be defined and calculated in quite different ways. It follows that the main problem of this chapter will be the clear definition of how a given σ value was obtained.

Otto Exner

Papers

The Chemistry of Hydroxamic Acids and N-Hydroxyimides

On the enthalpy-entropy-relationship

Additive physical properties. I. General relationships and problems of statistical nature

A Critical Compilation of Substituent Constants

Dipole moments in organic chemistry