Computational study of small molecule binding for both tethered and free conditions

TL;DR

This study compares the binding free energies of a calix[4]arene-benzene complex under tethered and free conditions in vacuum and water, highlighting the roles of entropy and enthalpy in binding differences.

Contribution

It provides a detailed analysis of how tethering affects binding energetics in different environments, informing nanosensor design.

Findings

In vacuum, tethering affects binding mainly through entropy, with a 6.5 kJ/mol difference.

In water, enthalpy dominates the tethering effect, with a 1.6 kJ/mol difference.

Tethering can significantly alter binding properties, impacting nanosensor applications.

Abstract

Using a calix[4]arene-benzene complex as a test system we compare the potential of mean force for when the calix[4]arene is tethered versus free. When the complex is in vacuum our results show that the difference between tethered and free is primarily due to the entropic contribution to the potential of mean force resulting in a binding free energy difference of 6.5 kJ/mol. By contrast, when the complex is in water our results suggest that the difference between tethered and free is due to the enthalpic contribution resulting in a binding free energy difference of 1.6 kJ/mol. This study elucidates the roles of entropy and enthalpy for this small molecule system and emphasizes the point that tethering the receptor has the potential to dramatically impact the binding properties. These findings should be taken into consideration when using calixarene molecules in nanosensor design.