Does SARS-CoV-2 Bind to Human ACE2 More Strongly Than Does SARS-CoV?

Area of Science:

• Molecular biology
• Virology
• Biophysics

Background:

• The 2019 novel coronavirus (SARS-CoV-2) pandemic poses a significant global threat.
• SARS-CoV-2 shares genetic similarity with SARS-CoV, the causative agent of a previous epidemic.
• Understanding the atomic-level interactions of SARS-CoV-2 is crucial for pandemic response.

Purpose of the Study:

• To investigate the binding mechanism between the receptor binding domain (RBD) of SARS-CoV and SARS-CoV-2 with the human angiotensin-converting enzyme 2 peptidase domain (ACE2-PD).
• To reconcile conflicting experimental data on the binding affinities of SARS-CoV-2 and SARS-CoV spike proteins to ACE2.
• To elucidate the driving forces behind the binding interactions at a molecular level.

Main Methods:

• Coarse-grained molecular modeling to calculate dissociation constants.
• Steered all-atom molecular dynamics simulations to assess binding strength.
• Analysis of electrostatic interactions governing the binding.

Main Results:

• SARS-CoV-2-RBD demonstrated a 2-fold higher binding affinity to human ACE2-PD compared to SARS-CoV-RBD.
• Steered molecular dynamics simulations confirmed stronger association of SARS-CoV-2-RBD with ACE2-PD, indicated by higher rupture force and pulling work.
• Electrostatic interactions were identified as the primary driver for the binding affinity of both viruses to ACE2.

Conclusions:

• SARS-CoV-2 exhibits a stronger binding affinity to human ACE2 than SARS-CoV, potentially contributing to its increased severity.
• Molecular modeling provides a mechanistic understanding of the differential binding affinities observed experimentally.
• Electrostatic forces play a critical role in the interaction between viral spike proteins and the ACE2 receptor.