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

• Published in: Cells (Basel, Switzerland) Vol. 11; no. 8; p. 1274
• Main Authors: Zhang, Zhi-Bi, Xia, Yuan-Ling, Shen, Jian-Xin, Du, Wen-Wen, Fu, Yun-Xin, Liu, Shu-Qun
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 09.04.2022; MDPI
• Subjects: ACE2; Affinity; amino acid residue changes; Angiotensin; Angiotensin-converting enzyme 2; Angiotensin-Converting Enzyme 2 - metabolism; binding free energy calculations; binding interfaces; Comparative analysis; Coronaviruses; COVID-19; electrostatic interactions; Electrostatic properties; Entropy; Free energy; Humans; Hydrogen bonding; Interfaces; molecular dynamics; Peptidyl-dipeptidase A; protein-protein binding affinity; Proteins; SARS Virus - metabolism; SARS-CoV-2 - metabolism; Severe acute respiratory syndrome coronavirus 2; Simulation; Spike Glycoprotein, Coronavirus - metabolism; Spike protein; binding interfaces; binding free energy calculations; amino acid residue changes; protein-protein binding affinity; molecular dynamics; electrostatic interactions
• ISSN: 2073-4409; 2073-4409
• DOI: 10.3390/cells11081274

The receptor-binding domain (RBD) of the SARS-CoV-2 spike protein (RBD ) has a higher binding affinity to the human receptor angiotensin-converting enzyme 2 (ACE2) than the SARS-CoV RBD (RBD ). 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 RBD -ACE2 complex, RBD -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 RBD determine the higher ACE2-binding affinity of RBD than of RBD . 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 RBD -ACE2, which not only tightens the interface packing and suppresses the dynamics of RBD -ACE2, but also enhances the ACE2-binding affinity of RBD . 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.