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Conserved Binding Sites

Conserved Binding Sites

Many proteins’ biological role depends on their interactions with their ligands, small molecules that bind to specific locations on the protein known as ligand-binding sites. Ligand-binding sites are often conserved among homologous proteins as these sites are critical for protein function.
Binding sites are often located in large pockets, and if their location on a protein’s surface is unknown, it can be predicted using various approaches. The energetic method computationally...

Conformations of Cyclohexane

Conformations of Cyclohexane

Cyclohexane does not exist in a planar form due to the high angle and torsional strain it would experience in the planar structure. Instead, it adopts non-planar chair and boat conformations.
The chair form is the most stable and derives its name from its resemblance to the “easy chair.” In the chair conformation, two carbon atoms are arranged out-of-plane — one above and one below, minimizing the torsional strain. In the chair form, the bond angle is very close to the ideal...

Chair Conformation of Cyclohexane

Chair Conformation of Cyclohexane

The chair conformation is the most stable form of cyclohexane due to the absence of angle and torsional strain. The absence of angle strain is a result of cyclohexane’s bond angle being very close to the ideal tetrahedral bond angle of 109.5° in its chair conformer. Similarly, the torsional strain is also absent owing to the perfectly staggered arrangement of bonds.
The hydrogen atoms linked to carbons are arranged in two different axial and equatorial orientations to achieve this...

¹H NMR of Conformationally Flexible Molecules: Temporal Resolution

¹H NMR of Conformationally Flexible Molecules: Temporal Resolution

At room temperature, the chair conformer of cyclohexane undergoes rapid ring flipping between two equivalent chair conformers at a rate of approximately 105 times per second. These two chair conformers are in equilibrium. The rapid ring flipping results in the interconversion of the axial proton to an equatorial proton and an equatorial to the axial proton. Such interconversions are too rapid and cannot be detected on the NMR timescale. Hence, the NMR spectrometer cannot distinguish between the...

The Equilibrium Binding Constant and Binding Strength

The Equilibrium Binding Constant and Binding Strength

The equilibrium binding constant (Kb) quantifies the strength of a protein-ligand interaction. Kb can be calculated as follows when the reaction is at equilibrium:

Conformations of Cycloalkanes

Conformations of Cycloalkanes

Adolf von Baeyer attempted to explain the instabilities of small and large cycloalkane rings using the concept of angle strain — the strain caused by the deviation of bond angles from the ideal 109.5° tetrahedral value for sp3 hybridized carbons. However, while cyclopropane and cyclobutane are strained, as expected from their highly compressed bond angles, cyclopentane is more strained than predicted, and cyclohexane is virtually strain-free. Hence, Baeyer’s theory that...

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Related Experiment Video

Updated: Mar 14, 2026

Interactive Molecular Model Assembly with 3D Printing

Interactive Molecular Model Assembly with 3D Printing

Published on: August 13, 2020

Predicting bioactive conformations and binding modes of macrocycles.

Andrew Anighoro¹, Antonio de la Vega de León¹, Jürgen Bajorath²

¹Department of Life Science Informatics, B-IT, LIMES Program Unit Chemical Biology and Medicinal Chemistry, Rheinische Friedrich-Wilhelms-Universität, Dahlmannstr. 2, 53113, Bonn, Germany.

Journal of Computer-Aided Molecular Design

|September 23, 2016

Summary

Predicting the binding of macrocyclic compounds in drug discovery is challenging. A new computational method combining conformational ensembles and rigid body docking improves the accuracy of predicting their bioactive conformations and binding modes.

Keywords:

Bioactive conformations Conformational analysis Docking Macrocycles Scoring Three-dimensional binding modes

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Area of Science:

Computational chemistry
Drug discovery
Molecular modeling

Background:

Macrocyclic compounds are increasingly important in drug discovery for targeting difficult proteins.
Current computational docking methods struggle with the conformational flexibility of macrocycles.

Purpose of the Study:

To develop and evaluate a computational protocol for predicting bioactive conformations and binding modes of macrocyclic compounds.
To assess the impact of conformational flexibility and docking strategies on prediction accuracy.

Main Methods:

Utilized specialized conformational search techniques to generate ensembles of macrocyclic conformations.
Employed rigid body docking on pre-computed conformational ensembles.
Analyzed the role of conformational energies and shape complementarity in binding mode prediction.

Main Results:

Conformational ensembles contained accurate bioactive conformations for ~70% of tested macrocycles, though not easily identified by energy alone.
Docking with limited flexibility from low-energy conformations yielded accurate binding modes in only ~40% of cases.
Rigid body docking of conformational ensembles improved meaningful binding mode predictions to over 50%.

Conclusions:

A combined computational protocol using conformational ensembles as a starting point for docking shows promise for modeling macrocyclic compounds.
Shape complementarity is a key factor in accurate binding mode prediction for macrocycles.
Pre-computation of conformational ensembles is crucial for improving docking accuracy.