Absolute Binding Free Energy Calculations for Highly Flexible Protein MDM2 and Its Inhibitors.

Nidhi Singh,Wenjin Li

doi:10.3390/ijms21134765

Abstract

Reliable prediction of binding affinities for ligand-receptor complex has been the primary goal of a structure-based drug design process. In this respect, alchemical methods are evolving as a popular choice to predict the binding affinities for biomolecular complexes. However, the highly flexible protein-ligand systems pose a challenge to the accuracy of binding free energy calculations mostly due to insufficient sampling. Herein, integrated computational protocol combining free energy perturbation based absolute binding free energy calculation with free energy landscape method was proposed for improved prediction of binding free energy for flexible protein-ligand complexes. The proposed method is applied to the dataset of various classes of p53-MDM2 (murine double minute 2) inhibitors. The absolute binding free energy calculations for MDMX (murine double minute X) resulted in a mean absolute error value of 0.816 kcal/mol while it is 3.08 kcal/mol for MDM2, a highly flexible protein compared to MDMX. With the integration of the free energy landscape method, the mean absolute error for MDM2 is improved to 1.95 kcal/mol.

Highlights

One of the major goals of structure-based drug design is accurate prediction of protein-ligand binding affinity
The computational study based upon principal component analysis of molecular dynamics trajectory by Joseph et al showed that apo-MDMX is less flexible as compared to apo-MDM2 [26]
Binding free energy calculations done by Hui Sun Lee et al supported that MDMX undergoes minimal changes upon ligand binding [28]

Summary

Introduction

One of the major goals of structure-based drug design is accurate prediction of protein-ligand binding affinity. Despite of the availability of lot of structural information of biological targets, the precise modelling of conformational changes of receptor upon ligand binding, entropy-enthalpy compensation, and solvent effects is a complex task [2,3]. To this end, the simulation-based computational methods have shown great promise in calculating the reliable binding free energy [4,5,6,7]. One ligand is converted to another by a series of alchemical transformations in the bound state and free in solution [1,8] This approach is better automated and widely applied. One of the most studied systems for absolute binding free energy calculations is the binding pocket of T4 lysozyme

Methods

Results

Conclusion