Mechanistic Origin of Different Binding Affinities of SARS-CoV and SARS-CoV-2 Spike RBDs to Human ACE2

Abstract

The receptor-binding domain (RBD) of the SARS-CoV-2 spike protein (RBDCoV2) has a higher binding affinity to the human receptor angiotensin-converting enzyme 2 (ACE2) than the SARS-CoV RBD (RBDCoV). Here, we performed molecular dynamics (MD) simulations, binding free energy (BFE) calculations, and interface residue contact network (IRCN) analysis to explore the mechanistic origin of different ACE2-binding affinities of the two RBDs. The results demonstrate that, when compared to the RBDCoV2-ACE2 complex, RBDCoV-ACE2 features enhanced dynamicsand inter-protein positional movements and increased conformational entropy and conformational diversity. Although the inter-protein electrostatic attractive interactions are the primary determinant for the high ACE2-binding affinities of both RBDs, the significantly enhanced electrostatic attractive interactions between ACE2 and RBDCoV2 determine the higher ACE2-binding affinity of RBDCoV2 than of RBDCoV. Comprehensive comparative analyses of the residue BFE components and IRCNs between the two complexes reveal that it is the residue changes at the RBD interface that lead to the overall stronger inter-protein electrostatic attractive force in RBDCoV2-ACE2, which not only tightens the interface packing and suppresses the dynamics of RBDCoV2-ACE2, but also enhances the ACE2-binding affinity of RBDCoV2. Since the RBD residue changes involving gain/loss of the positively/negatively charged residues can greatly enhance the binding affinity, special attention should be paid to the SARS-CoV-2 variants carrying such mutations, particularly those near or at the binding interfaces with the potential to form hydrogen bonds and/or salt bridges with ACE2.

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 detailed comparison of various BFE terms and short-range interaction energies of RBD WT -ACE2 and RBD OMI s-ACE2 complexes indicates that, when compared with vdW interactions and hydrophobic effects, the electrostatic attractive interactions are the primary determinant of the enhanced binding affinity of RBD to ACE2. In addition, when comparing SARS-CoV-2 and SARS-CoV, the identical conclusion was obtained, that is, the electrostatic attractive interactions primarily determine the higher ACE2-binding affinity of RBD of the former, than the latter [ 8 ]. Although SARS-CoV-2 is unlikely to have evolved directly from SARS-CoV, we can also infer that it may be because the previous generation of SARS-CoV-2 acquired mutations that significantly enhanced its electrostatic attractive interactions with human ACE2 to the point that it finally evolved the ability to infect humans.…”

“…Currently, the Omicron BA.4 and BA.5 have replaced BA.2 as the dominant SARS-CoV-2 strains due to their high transmissibility [ 36 ]. The high transmissibility of the new SARS-CoV-2 variants may be attributed to its spike RBD being more likely to be “up” state, which can facilitate the binding (or interaction) of spike and ACE2 [ 8 , 37 ]. For example, a recently study by Sztain et al showed that the glycosylation of several residues of RBD can facilitate RBD opening and to be “up” state [ 38 ].…”

“…In this study, the MM-PBSA algorithm [ 62 ] was used to calculate the BFE between ACE2 and RBD. MM-PBSA is a well-known endpoint approach which can estimate the protein-ligand BFE based merely on the structure or structural ensemble of the bound complex without considering either the physical or the non-physical intermediates [ 8 , 63 , 64 ]. In MM-PBSA, the BFE of the protein and ligand is defined as: Δ G binding = Δ G complex − (Δ G protein + Δ G ligand ) …”

“…The RBD can be further divided into a core region consisting of five antiparallel β-sheet and seven α-helix, and a receptor binding motif (RBM) ( Figure 1 B), which are located at the contact region of the spike and ACE2. Previous studies have shown that when compared with SARS-CoV, the changes of some key residues in the RBD of the SARS-CoV-2 spike protein can enhance its binding affinity to ACE2, which causes SARS-CoV-2 to be more infectious than SARS-CoV [ 3 , 8 , 9 , 10 , 11 ].…”

Identification of and Mechanistic Insights into SARS-CoV-2 Main Protease Non-Covalent Inhibitors: An In-Silico Study

“…Further MD simulations revealed that ML188 and ECI2-4 kept staying within the substrate-binding cavity of Mpro during the entire simulation period, while ECI1 (which has the lowest/best docking score value among the five inhibitors; see Table S2 ) escaped out of the cavity. This is not surprising, as the optimal docking pose of a ligand (i.e., the pose with the best docking score) does not necessarily represent the actual binding poses within the protein target, whose space could be sampled by the all-atom MD simulation with a more sophisticated force field under explicit conditions (e.g., solvent, pH, salt concentration, temperature, and pressure) [ 66 , 67 , 68 , 69 ]. Our results highlight that the MD simulation following the molecular docking is necessary for assessing the complex stability and optimizing the inter-molecular binding mode.…”