An Effective MM/GBSA Protocol for Absolute Binding Free Energy Calculations: A Case Study on SARS-CoV-2 Spike Protein and the Human ACE2 Receptor.

Negin Forouzesh,Nikita Mishra

doi:10.3390/molecules26082383

Abstract

The binding free energy calculation of protein–ligand complexes is necessary for research into virus–host interactions and the relevant applications in drug discovery. However, many current computational methods of such calculations are either inefficient or inaccurate in practice. Utilizing implicit solvent models in the molecular mechanics generalized Born surface area (MM/GBSA) framework allows for efficient calculations without significant loss of accuracy. Here, GBNSR6, a new flavor of the generalized Born model, is employed in the MM/GBSA framework for measuring the binding affinity between SARS-CoV-2 spike protein and the human ACE2 receptor. A computational protocol is developed based on the widely studied Ras–Raf complex, which has similar binding free energy to SARS-CoV-2/ACE2. Two options for representing the dielectric boundary of the complexes are evaluated: one based on the standard Bondi radii and the other based on a newly developed set of atomic radii (OPT1), optimized specifically for protein–ligand binding. Predictions based on the two radii sets provide upper and lower bounds on the experimental references: kcal/mol. The consensus estimates of the two bounds show quantitative agreement with the experiment values. This work also presents a novel truncation method and computational strategies for efficient entropy calculations with normal mode analysis. Interestingly, it is observed that a significant decrease in the number of snapshots does not affect the accuracy of entropy calculation, while it does lower computation time appreciably. The proposed MM/GBSA protocol can be used to study the binding mechanism of new variants of SARS-CoV-2, as well as other relevant structures.

Highlights

Emerging as a global threat to human health, the SARS-CoV-2 virus that causes the COVID-19 disease has been widely studied since early 2020 [1]
To test the accuracy of the proposed truncation algorithm, Normal-mode analysis (NMA) entropy was calculated on three truncated structures of the Ras–Raf, as follows: the binding interface of the complex was found through visualization, and the residues of the Ras protein within
After adjusting for concentration dependence, each of the three simulations gave a − the solute (T∆S) value of 37.26 ± 3.21 kcal/mol. These results indicate that so long as the binding interface remains conserved and the structures are continuous, truncating protein structures do not impact the validity of NMA calculations

Summary

Introduction

Emerging as a global threat to human health, the SARS-CoV-2 virus that causes the COVID-19 disease has been widely studied since early 2020 [1]. This fast-growing pandemic highlights the role of computational structural biology and computer-aided drug design (CADD), which have the ability to accelerate the slow and expensive process of drug discovery [2]. In structure-based drug discovery, the accuracy and speed of binding free energy estimations of drug-like compounds (ligands) to target biomolecules plays a key role in virtual screening of drug candidates [7,8,9]. The binding free energy of a molecular system can be estimated directly from thermodynamic first principles [15]

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Conclusion