All-Atom Simulations of Human ACE2-Spike Protein RBD Complexes for SARS-CoV-2 and Some of its Variants: Nature of Interactions and Free Energy Diagrams for Dissociation of the Protein Complexes

Abstract

The spike protein of SARS-CoV-2 is known to interact with the human ACE2 protein via its receptor binding domain (RBD). We have investigated the molecular nature of this interprotein interaction and the associated free energy diagrams for the unbinding of the two proteins for SARS-CoV-2 and some of its known variants through all-atom simulations. The present work involves generation and analysis of 2.5 μs of unbiased and 4.2 μs of biased molecular dynamics trajectories in total for five explicitly solvated RBD-ACE2 systems at full atomic level. First, we have made a comparative analysis of the details of residue-wise specific interactions of the spike protein with ACE2 for SARS-CoV-1 and SARS-CoV-2. It is found that the average numbers of both direct interprotein and water-bridged hydrogen bonds between the RBD and ACE2 are higher for SARS-CoV-2 than SARS-CoV-1. These higher hydrogen bonded interactions are further aided by enhanced nonspecific electrostatic attractions between the two protein surfaces for SARS-CoV-2. The free energy calculations reveal that there is an increase in the free energy barrier by ∼1.5 kcal/mol for the unbinding of RBD from ACE2 for SARS-CoV-2 compared to that for SARS-CoV-1. Subsequently, we considered the RBDs of three variants of SARS-CoV-2, namely N501Y, E484Q/L452R, and N440K. The free energy barrier of protein unbinding for the N501Y variant is found to be ∼4 kcal/mol higher than the wild type SARS-CoV-2 which can be attributed to additional specific interactions involving Tyr501 of RBD and Lys353 and Tyr42 of ACE2 and also enhanced nonspecific electrostatic interaction between the protein surfaces. For the other two mutant variants of E484Q/L452R and N440K, the free energy barrier for protein unbinding increases by ∼2 and ∼1 kcal/mol, respectively, compared with the wild type SARS-CoV-2, which can be attributed to an increase in the number of interprotein hydrogen bonds for the former and also to enhanced positive electrostatic potential on the RBD surfaces for both of the variants. The successive breaking of interprotein hydrogen bonds along the free energy pathway of the unbinding process is also found out for all five systems studied here.

Electrostatic Interactions Are the Primary Determinant of the Binding Affinity of SARS-CoV-2 Spike RBD to ACE2: A Computational Case Study of Omicron Variants

“…The comparison between BFEs of RBD WT -ACE2 and RBD OMI s-ACE2 complexes indicates that all RBD OMI s have a more enhanced ACE2-binding affinity than RBD WT , which is consistent with the former studies [ 28 , 29 , 30 ]. It is worth pointing out that all Omicron variants have lager BSAs at the RBD-ACE2 interface than WT, providing a positive correlation between enhanced BFE and larger BSA.…”

“…Multiple previous studies show that the RBD OMI s have a higher binding affinity to ACE2 than that of RBD WT , which can provide a reasonable explanation for the high transmissibility of the Omicron variant [ 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 ]. However, differences in RBD-ACE2 binding affinity between the individual Omicron subvariants and the underlying mechanisms have not been well studied.…”

Energetics of Spike Protein Opening of SARS-CoV-1 and SARS-CoV-2 and Its Variants of Concern: Implications in Host Receptor Scanning and Transmission

“…This may explain large differences in ACE2 affinity between RBD CoV-1 and RBD CoV-2 determined experimentally 2,25 or using computational calculations. 29,30 We further reasoned that variations in contact properties of RBDs CoV-1 and RBDs CoV-2, which were predominantly localized in the S1 domain can differentially contribute to PPI and thus modulate host receptor engagement of S proteins. This was ascertained during MD simulations where an increase in RBD contacts resulted in differential increase in average (PPI) binding energy of RBD CoV-1 and RBD CoV-2 with neighboring S1 and S2 domains.…”

Electrostatic Features for the Receptor Binding Domain of SARS-COV-2 Wildtype and Its Variants. Compass to the Severity of the Future Variants with the Charge-Rule

“…A large number of papers have shown that electrostatic interactions are indeed very important for SARS-CoV-2 (e.g., refs , , , and − ). Most of the studies have focused on the interactions involving the receptor-binding domain (RBD) of the SARS-CoV-2 spike homotrimer glycoprotein due to its biological central relevance.…”