Calculation of Crystal-Solution Dissociation Constants.

Sergiy O Garbuzynskiy,Alexei V Finkelstein

doi:10.3390/biom12020147

Abstract

The calculation of dissociation constants is an important problem in molecular biophysics. For such a calculation, it is important to correctly calculate both terms of the binding free energy; that is, the enthalpy and entropy of binding. Both these terms can be computed using molecular dynamics simulations, but this approach is very computationally expensive, and entropy calculations are especially slow. We develop an alternative very fast method of calculating the binding entropy and dissociation constants. The main part of our approach is based on the evaluation of movement ranges of molecules in the bound state. Then, the range of molecular movements in the bound state (here, in molecular crystals) is used for the calculation of the binding entropies and, then (using, in addition, the experimentally measured sublimation enthalpies), the crystal-to-vapor dissociation constants. Previously, we considered the process of the reversible sublimation of small organic molecules from crystals to vapor. In this work, we extend our approach by considering the dissolution of molecules, in addition to their sublimation. Similar to the sublimation case, our method shows a good correlation with experimentally measured dissociation constants at the dissolution of crystals.

Highlights

For such a calculation, it is important to correctly calculate both terms of the binding free energy; that is, the enthalpy and entropy of binding
Similar to the sublimation case, our method shows a good correlation with experimentally measured dissociation constants at the dissolution of crystals
In previous works [25–27], we considered a simple case of the equilibrium between molecular crystals and vapor

Summary

Introduction

It is important to correctly calculate both terms of the binding free energy; that is, the enthalpy and entropy of binding. The range of molecular movements in the bound state (here, in molecular crystals) is used for the calculation of the binding entropies and, (using, in addition, the experimentally measured sublimation enthalpies), the crystal-to-vapor dissociation constants. Some researchers focus on the enthalpy component of the free energy of binding [4–7], while others suggest that the main obstacle to a satisfactory estimate of the free energy of binding is the difficulty of taking into account its entropy component [8,9]. Both terms that compose binding free energy (enthalpy and entropy) can, in principle, be estimated by molecular dynamics methods [10,11]. The entropy of binding can be estimated [13] by tracing a very long (until reaching a thermodynamic equilibrium) molecular dynamic trajectory of the motion of all atoms in a complex of bound molecules (for example, in a protein–ligand complex), and in these molecules taken separately

Methods

Results

Conclusion