Why Does the Novel Coronavirus Spike Protein Interact so Strongly with the Human ACE2? A Thermodynamic Answer

The SARS‐CoV‐2 pandemic is the biggest health concern today, but until now there is no treatment. One possible drug target is the receptor binding domain (RBD) of the coronavirus’ spike protein, which recognizes the human angiotensin‐converting enzyme 2 (hACE2). Our in silico study discusses crucial structural and thermodynamic aspects of the interactions involving RBDs from the SARS‐CoV and SARS‐CoV‐2 with the hACE2. Molecular docking and molecular dynamics simulations explain why the chemical affinity of the new SARS‐CoV‐2 for hACE2 is much higher than in the case of SARS‐CoV, revealing an intricate pattern of hydrogen bonds and hydrophobic interactions and estimating a free energy of binding, which is consistently much more negative in the case of SARS‐CoV‐2. This work presents a chemical reason for the difficulty in treating the SARS‐CoV‐2 virus with drugs targeting its spike protein and helps to explain its infectiousness. The receptor binding domain (RBD) from coronavirus’ spike protein recognizes human angiotensin‐converting enzyme 2 (hACE2), making it an important drug target. This in silico study compares RBD interactions from SARS‐CoV and SARS‐CoV‐2 with the hACE2, revealing an intricate pattern of hydrogen bonds and hydrophobic interactions, and a free energy of binding consistently stronger for the later virus.