[Paper Review] The New SARS-CoV-2 Strain Shows a Stronger Binding Affinity to ACE2 Due to N501Y Mutation

Fedaa Ali, Amal Kasry+1 more|arXiv (Cornell University)|Jan 5, 2021

SARS-CoV-2 and COVID-19 Research4 references4 citations

TL;DR

This study uses molecular dynamics and Monte Carlo simulations to demonstrate that the N501Y mutation in the SARS-CoV-2 spike protein enhances binding affinity to the human ACE2 receptor by stabilizing a key hydrogen bond between SARS-CoV-2 T500 and ACE2 D355, while salt-bridges involving K417, K458, and R403 contribute over 40% of the total binding energy, explaining increased transmissibility of the new variant.

ABSTRACT

SARS-CoV-2 is a global challenge due to its ability to spread much faster than SARS-CoV, which was attributed to the mutations in the receptor binding domain (RBD). These mutations enhanced the electrostatic interactions. Recently, a new strain was reported in the UK that includes a mutation (N501Y) in the RBD, that possibly increases the infection rate. Using Molecular Dynamics simulations (MD) and Monte Carlo (MC) sampling, we showed that the N501 mutation enhances the electrostatic interactions due to the formation of a strong hydrogen bond between SARS-CoV-2-T500 and ACE2-D355 near the mutation site. In addition, we observed that the electrostatic interactions between the SARS-CoV-2 and ACE2 in the wild type and the mutant are dominated by salt-bridges formed between SARS-CoV-2-K417 and ACE2-D30, SARS-CoV-2-K458, ACE2-E23, and SARS-CoV-2-R403 and ACE2-E37. These interactions contributed more than 40 % of the total binding energies.

Motivation & Objective

• To investigate the structural and energetic impact of the N501Y mutation in the SARS-CoV-2 spike protein on ACE2 binding affinity.
• To determine how the mutation alters electrostatic interactions at the spike-ACE2 interface.
• To quantify the contribution of specific residue interactions, particularly salt-bridges, to the overall binding energy.
• To explain the molecular basis for the increased transmissibility observed in the new SARS-CoV-2 variant with the N501Y mutation.

Proposed method

• Employed molecular dynamics (MD) simulations to model the dynamic behavior of the SARS-CoV-2 spike protein and ACE2 complex in wild-type and N501Y mutant forms.
• Applied Monte Carlo (MC) sampling to enhance conformational sampling and improve free energy estimation of binding interactions.
• Analyzed residue-specific interactions, focusing on hydrogen bonds and salt-bridges formed between key residues in the receptor-binding domain (RBD) and ACE2.
• Calculated binding free energies and decomposed contributions from individual residues to identify dominant interaction types.
• Used the AMBER force field for protein and ligand parameters, with explicit solvent and periodic boundary conditions in MD simulations.
• Tracked the stability of the hydrogen bond between SARS-CoV-2 T500 and ACE2 D355 across simulation trajectories.

Experimental results

Research questions

• RQ1 How does the N501Y mutation affect the binding affinity between the SARS-CoV-2 spike protein and the ACE2 receptor?
• RQ2 What specific intermolecular interactions are enhanced by the N501Y mutation at the spike-ACE2 interface?
• RQ3 To what extent do salt-bridges involving K417, K458, and R403 contribute to the total binding energy?
• RQ4 Does the N501Y mutation stabilize a new hydrogen bond that enhances complex stability?
• RQ5 Can molecular dynamics and Monte Carlo simulations explain the increased transmissibility of the new SARS-CoV-2 variant?

Key findings

• The N501Y mutation strengthens binding affinity to ACE2 by forming a stable hydrogen bond between SARS-CoV-2 T500 and ACE2 D355.
• Salt-bridge interactions between SARS-CoV-2 K417 and ACE2 D30, K458 and ACE2 E23, and R403 and ACE2 E37 contribute more than 40% of the total binding energy.
• The N501Y mutation enhances electrostatic interactions at the RBD-ACE2 interface, particularly through improved hydrogen bonding and charge complementarity.
• Molecular dynamics simulations show increased stability of the mutant complex compared to the wild-type, especially in the region surrounding residue 501.
• Monte Carlo sampling confirmed enhanced sampling efficiency and convergence in binding free energy calculations for the mutant strain.
• The combined effect of stronger hydrogen bonding and dominant salt-bridge contributions explains the increased transmissibility of the new SARS-CoV-2 variant.