Towards an understanding of the molecular basis of hydrophobicity

Mancera, Ricardo L.

doi:10.1007/bf00124501

Cited by 10 publications

(5 citation statements)

References 28 publications

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“…An alternative approach does not regard the structuring of the water molecules as the main reason for hydrophobic interactions. Instead, it involves a positive enthalpy resulting from the rupture of several hydrogen bonds in order to create a cavity in the water structure that subsequently accommodates the nonpolar compound 306, 307. In agreement with this hypothesis, calorimetric measurements found that contributions of 25–100 % of the protein–ligand binding enthalpy originate from solvent reorganization 308…”

Section: Binding Affinity As a Results Of Inter‐ And Intramolecularmentioning

confidence: 74%

Approaches to the Description and Prediction of the Binding Affinity of Small-Molecule Ligands to Macromolecular Receptors

Gohlke

Klebe

2002

Angew. Chem. Int. Ed.

759

674

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The influence of a xenobiotic compound on an organism is usually summarized by the expression biological activity. If a controlled, therapeutically relevant, and regulatory action is observed the compound has potential as a drug, otherwise its toxicity on the biological system is of interest. However, what do we understand by the biological activity? In principle, the overall effect on an organism has to be considered. However, because of the complexity of the interrelated processes involved, as a simplification primarily the "main action" on the organism is taken into consideration. On the molecular level, biological activity corresponds to the binding of a (low-molecular weight) compound to a macromolecular receptor, usually a protein. Enzymatic reactions or signal-transduction cascades are thereby influenced with respect to their function for the organism. We regard this binding as a process under equilibrium conditions; thus, binding can be described as an association or dissociation process. Accordingly, biological activity is expressed as the affinity of both partners for each other, as a thermodynamic equilibrium quantity. How well do we understand these terms and how well are they theoretically predictable today? The holy grail of rational drug design is the prediction of the biological activity of a compound. The processes involving ligand binding are extremely complicated, both ligand and protein are flexible molecules, and the energy inventory between the bound and unbound states must be considered in aqueous solution. How sophisticated and reliable are our experimental approaches to obtaining the necessary insight? The present review summarizes our current understanding of the binding affinity of a small-molecule ligand to a protein. Both theoretical and empirical approaches for predicting binding affinity, starting from the three-dimensional structure of a protein-ligand complex, will be described and compared. Experimental methods, primarily microcalorimetry, will be discussed. As a perspective, our own knowledge-based approach towards affinity prediction and experimental data on factorizing binding contributions to protein-ligand binding will be presented.

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Section: Binding Affinity As a Results Of Inter‐ And Intramolecularmentioning

confidence: 74%

Approaches to the Description and Prediction of the Binding Affinity of Small-Molecule Ligands to Macromolecular Receptors

Gohlke

Klebe

2002

Angew. Chem. Int. Ed.

759

674

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“…Several years ago, Muller proposed his modified hydration-shell hydrogen-bond model to calculate the contributions to the thermodynamics of hydration from the formation of hydrogen bonds between water molecules in the hydration shell of nonpolar substances. , His simple model predicted that hydration-shell hydrogen bonds would have higher bond-breaking enthalpies and entropies than those in pure water and that it manifested itself by the existence of a larger fraction of broken hydrogen bonds in the hydration shell than in the bulk. , Such predictions about the fraction of broken hydrogen bonds were later confirmed by computer simulations. − …”

Section: Introductionmentioning

confidence: 99%

“…16,8 Such predictions about the fraction of broken hydrogen bonds were later confirmed by computer simulations. [17][18][19] A series of simulations of solutions of methane in both pure and salt (NaCl) water have been reported recently, showing for the first time the existence of an enhanced hydrophobicity in the presence of salt. 20,21 In this paper we report the results of using Muller's modified hydration-shell hydrogen-bond model to compute and contrast the hydrogen-bond contributions to hydrophobic hydration in pure and saltwater.…”

Section: Introductionmentioning

confidence: 99%

Influence of Salt on Hydrophobic Effects: A Molecular Dynamics Study Using the Modified Hydration-Shell Hydrogen-Bond Model

Mancera

1999

J. Phys. Chem. B

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Molecular dynamics computer simulations of solutions of methane in pure and saltwater have been performed, followed by an analysis of the properties of the hydrogen bonds in the solutions. Following the modified hydration-shell hydrogen-bond model of hydrophobic hydration, it is confirmed that in pure water the formation of hydrogen bonds between water molecules in the hydration shell of nonpolar solutes is enthalpically favored and entropically unfavored, with a net positive contribution to the free energy. By contrast, in saltwater, the formation of these same hydrogen bonds in the vicinity of the nonpolar solutes is now enthalpically unfavored and entropically favored, while the contribution to the free energy is even more positive. In pure water, the hydration-shell hydrogen-bonding contribution to the heat capacity of solution is always positive; in saltwater, this contribution is positive at low temperatures but decreases sharply and becomes negative at higher temperatures.

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“…Allerdings ist diese klassische Sichtweise nicht allgemein akzeptiert 298, 302. Ein alternativer Ansatz sieht nicht in der Strukturierung der Wassermoleküle die Ursache für hydrophobe Wechselwirkungen, sondern in einer positiven Enthalpie bedingt durch das Aufbrechen von H‐Brücken zur Bildung einer Kavität im Wasser, die anschließend die unpolare Substanz aufnimmt 306, 307. Dementsprechend wurden in kalorimetrischen Studien Beiträge von 25 bis 100 % der Bindungsenthalpie von Liganden an Proteine bedingt durch Lösungsmittelreorganisation bestimmt 308…”

Section: Bindungsaffinität Als Resultat Inter‐ Und Intramolekulareunclassified

Ansätze zur Beschreibung und Vorhersage der Bindungsaffinität niedermolekularer Liganden an makromolekulare Rezeptoren

Gohlke

Klebe

2002

Angew. Chem.

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Der Einfluss einer körperfremden Verbindung auf einen Organismus wird in aller Regel an dem Begriff der biologischen Aktivität festgemacht. Liegt eine gezielte, therapeutisch relevante und regulierende Wirkung vor, so hat die Verbindung das Potenzial zu einem Arzneistoff, andernfalls betrachtet man ihren toxikologischen Einfluss auf das biologische System. Doch was versteht man unter dem Begriff der biologischen Aktivität? Natürlich ist an dieser Stelle der gesamte Effekt auf einen Organismus zu betrachten, doch wegen der Komplexität der ineinandergreifenden Vorgänge betrachtet man zunächst nur die „Hauptwirkung“ auf den Organismus. Auf die molekulare Ebene übertragen, bedeutet biologische Aktivität die Bindung einer (niedermolekularen) Verbindung an einen makromolekularen Rezeptor, in aller Regel ein Protein. Dadurch werden enzymatische Reaktionen oder Signaltransduktionskaskaden in ihrer Funktion für den Organismus beeinflusst. Wir betrachten diese Bindung als einen Vorgang unter Gleichgewichtsbedingungen, sodass sich die Bindung als Assoziations‐ oder Dissoziationsvorgang beschreiben lässt. Somit wird biologische Aktivität als Affinität der beiden Partner zueinander in Form einer thermodynamischen Gleichgewichtsgröße ausgedrückt. Wie gut sind diese Begriffe heute verstanden und theoretisch vorhersagbar? Kern des rationalen Wirkstoffdesigns ist die Vorhersage der biologischen Aktivität einer Verbindung. Die Vorgänge bei der Ligandenbindung sind äußerst komplex, sowohl Ligand als auch Protein sind flexible Moleküle, und die Energiebilanz muss zwischen getrenntem und gebundenem Zustand in wässriger Umgebung betrachtet werden. Wie ausgereift und aussagekräftig sind unsere experimentellen Verfahren, um hier die notwendigen Einblicke zu gewinnen? Der vorliegende Aufsatz fasst den derzeitigen Kenntnisstand zur Bindungsaffinität eines niedermolekularen Liganden zu einem Protein zusammen. Es werden theoretische wie empirische Ansätze beschrieben und gegenübergestellt, die eine Vorhersage der Bindungsaffinität aus der Raumstruktur eines Protein‐Ligand‐Komplexes zum Ziel haben. Experimentelle Ansätze, vor allem die Mikrokalorimetrie, werden diskutiert. Als Ausblick werden ein eigenes wissensbasiertes Verfahren zur Affinitätsvorhersage und experimentelle Daten zur Faktorisierung von Bindungsbeiträgen zur Ligandenbindung an Proteine vorgestellt.

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Towards an understanding of the molecular basis of hydrophobicity

Cited by 10 publications

References 28 publications

Approaches to the Description and Prediction of the Binding Affinity of Small-Molecule Ligands to Macromolecular Receptors

Approaches to the Description and Prediction of the Binding Affinity of Small-Molecule Ligands to Macromolecular Receptors

Influence of Salt on Hydrophobic Effects: A Molecular Dynamics Study Using the Modified Hydration-Shell Hydrogen-Bond Model

Ansätze zur Beschreibung und Vorhersage der Bindungsaffinität niedermolekularer Liganden an makromolekulare Rezeptoren

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