  The spread of the coronavirus disease 2019 (COVID-19) caused by severe acute
respiratory syndrome coronavirus-2 (SARS-CoV-2) has become a global health
crisis. The binding affinity of SARS-CoV-2 (in particular the receptor binding
domain, RBD) to its receptor angiotensin converting enzyme 2 (ACE2) and the
antibodies is of great importance in understanding the infectivity of COVID-19
and evaluating the candidate therapeutic for COVID-19. In this work, we propose
a new method based on molecular mechanics/Poisson-Boltzmann surface area
(MM/PBSA) to accurately calculate the free energy of SARS-CoV-2 RBD binding to
ACE2 and antibodies. The calculated binding free energy of SARS-CoV-2 RBD to
ACE2 is -13.3 kcal/mol, and that of SARS-CoV RBD to ACE2 is -11.4 kcal/mol,
which agrees well with experimental result (-11.3 kcal/mol and -10.1 kcal/mol,
respectively). Moreover, we take two recently reported antibodies as the
example, and calculate the free energy of antibodies binding to SARS-CoV-2 RBD,
which is also consistent with the experimental findings. Further, within the
framework of the modified MM/PBSA, we determine the key residues and the main
driving forces for the SARS-CoV-2 RBD/CB6 interaction by the computational
alanine scanning method. The present study offers a computationally efficient
and numerically reliable method to evaluate the free energy of SARS-CoV-2
binding to other proteins, which may stimulate the development of the
therapeutics against the COVID-19 disease in real applications.

Biomolecules;Biological Physics