Critical Reflections on the Hydrophobic Effect, its Origins and Manifestation: Water Structure, Chemical Reactivity, Micelles and Gels.

Chandrasekhar, S.

doi:10.18596/jotcsa.328983

Cited by 3 publications

(10 citation statements)

References 19 publications

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“…The hydrophobic effect has its origins in the greater solubility of an organic molecule in a non-polar solvent relative to water [16]. In the context of enzyme catalysis, the hydrophobic effect arises as the active site cleft provides a hydrophobic environment.…”

Section: The Hydrophobic Effectmentioning

confidence: 99%

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Understanding Enzymic Reactivity – New Directions and Approaches

Chandrasekhar

2020

AJRB

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New approaches towards understanding the reactivity of enzymes–central to chemical biology and a key to comprehending life itself–are discussed herein. The approach overall is based on the idea that structural and reactivity features uniquely characteristic of enzymes–in being absent in normal catalysts–are likely to hold the key to the catalytic powers of enzymes. The quintessentially physical-organic problem is addressed from several angles, both kinetic and phenomenological. (Generally, the Pauling theory of transition state stabilization is adopted as the rigorous basis for understanding enzyme action). The kinetic approach focuses on the inadequacies of the Michaelis-Menten equation, and proposes an alternative model based on additional substrate binding at high concentrations, which satisfactorily explains experimental observations. The phenomenological approaches focus on the inadequacies of the intramolecularity criterion, thus leading to alternative strategies adopted by nature in the design of these mild yet powerful catalysts, characterized by exquisite selectivity. Preferential transition state binding at the active site, via both hydrophobic and van der Waals forces, appears to be the major thermodynamic driver of enzymic reactivity. In operational terms, however, multifunctional catalysis–practically unique to the highly ordered enzyme interior–is likely the key to enzymic reactivity. A new concept, ‘strain delocalization’, possibly plays an important role in orchestrating these various effects, and indeed justifies the need for a large proteinic molecule for achieving the enormous rate enhancements generally observed with enzymes. Thus, this renewed approach to understanding enzymic reactivity departs significantly from currently held views: radically, in abandoning the Michaelis-Menten and intramolecularity models; but also commandeering existing ideas and concepts, although with a shift in emphasis towards transition state effects (including the entirely novel idea of ‘strain delocalization’).The coverage is not exhaustive, but aims to introduce new ideas along with fresh insights into previous works.

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Section: The Hydrophobic Effectmentioning

confidence: 99%

“…In fact, the role of the hydrophobic effect in nonenzymic reactions is complex and controversial [16]. This is essentially because the hydrophobic effect is largely nullified by the low solubility of the substrate in water.…”

Section: The X Axis Represents the Reaction Coordinate And The Y Axismentioning

confidence: 99%

Understanding Enzymic Reactivity – New Directions and Approaches

Chandrasekhar

2020

AJRB

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“…The "hydrophobic effect" refers to the scientific study of the common-sense notion that oil and water are immiscible. The recognition that the hydrophobic effect could be the key to a better understanding of a wide swath of chemical and biological phenomena apparently dates back to 1945, when the term itself was coined [1]. Currently, the hydrophobic effect is widely accepted as a critical conceptual bridge between chemistry and biology that-despite elements of confusion and controversy-brings together diverse experimental observations under its unifying ambit.…”

Section: Introductionmentioning

confidence: 99%

“…All the same, the hydrophobic effect has not been without controversy [1]. In particular, the origins of the hydrophobic effect have been confounded by the terminology employed, as it seems to imply a repulsive effect in a rather absolute sense.…”

Section: Introductionmentioning

confidence: 99%

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The Hydrophobic Effect in Chemistry, Biology and Medicine: An Update

Chandrasekhar

2021

AJOCS

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The roots of the hydrophobic effect (HE) apparently lie in certain chemical principles, although it has far-reaching implications across a swath of chemical biology. In particular, the HE drives the formation of micelles, the catalytic properties of which are believed to model the action of enzymes. The HE is also believed to be the key to drug-receptor interactions as captured in the Hansch equation and enshrined in QSAR. Yet, the HE remains paradoxical: The attributed medium effects apparently contravene normal experience, as apolar solvents are rarely (if ever) the preferred choice in practice! Indeed, the HE is complex and varied in its manifestations, affecting both structure and reactivity. The latter “kinetic hydrophobic effect” itself exists as “Types 1 and 2”, referring to reactions in water (e.g., Diels Alder) and non-aqueous media (e.g., micelles) respectively. Micellar reactivity also remains mysterious as, apparently, the HE only facilitates the formation of the micelles. The idea that micellar reactivity arises from concentration effects, in fact, appears simplistic for several reasons. Furthermore, reactions may well occur on the micellar surface, particularly with ionic reagents that would be poorly soluble in the core. There are important differences between micelles and enzymes: Enzymes are pre-configured with catalytic groups and charge-relay systems, although the contribution of the HE to activity remains uncertain. Micelles also form a separate phase, hence defining the thermodynamic ground state of the reactants (contrasting with enzymes). Certain aspects of the Hansch equation, particularly the decline of drug activity beyond the “Goldilocks zone” peak, are intriguing. However, a kinetic model of drug-receptor interactions based on the rates of drug binding and release, offers an explanation for the observations, also leading to further insights into the nature of the binding itself.

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Supramolecular Catalysis of a Catalysis-Resistant Diels–Alder Reaction: Almost Theoretical Acceleration of Cyclopentadiene Dimerization inside Cucurbit[7]uril

et al. 2022

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In contrast to Diels−Alder reactions involving heteroatom-containing substrates, the endo dimerization of cyclopentadiene responds only very weakly to changes in the microenvironment or the presence of potential catalysts (less than a factor of 10 variations). This pure hydrocarbon reaction has been used as an early model to predict the maximum possible catalytic effect (k cat /k uncat ca. 10 6 M) due to entropic contributions of transition-state confinement [

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Critical Reflections on the Hydrophobic Effect, its Origins and Manifestation: Water Structure, Chemical Reactivity, Micelles and Gels.

Cited by 3 publications

References 19 publications

Understanding Enzymic Reactivity – New Directions and Approaches

Understanding Enzymic Reactivity – New Directions and Approaches

The Hydrophobic Effect in Chemistry, Biology and Medicine: An Update

Supramolecular Catalysis of a Catalysis-Resistant Diels–Alder Reaction: Almost Theoretical Acceleration of Cyclopentadiene Dimerization inside Cucurbit[7]uril

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