Evolutionary trajectory of receptor binding specificity and promiscuity of the spike protein of SARS-CoV-2

• Published in: bioRxiv 2022-09
• Main Authors: Planchais, Cyril, Reyes-Ruiz, Alejandra, Lacombe, Robin, Zarantonello, Alessandra, Lecerf, Maxime, Revel, Margot, Roumenina, Lubka T, Atanasov, Boris P, Mouquet, Hugo, Dimitrov, Jordan D
• Format: Article
• Language: English
• Subjects: ACE2; Angiotensin; Angiotensin-converting enzyme 2; Computer applications; Electrostatic properties; Evolution; Immune response; Infectivity; Peptidyl-dipeptidase A; Proteins; Severe acute respiratory syndrome coronavirus 2; Spike protein; Tropism
• DOI: 10.1101/2022.06.11.495733

SARS-CoV-2 infects cells by attachment to its receptor the angiotensin converting enzyme 2 (ACE2). Regardless of the wealth of structural data, little is known about the physicochemical mechanism of interactions of the viral spike (S) protein with ACE2 and how this mechanism has evolved during the pandemic. Here, we applied experimental and computational approaches to characterize the molecular interaction of S proteins from SARS-CoV-2 variants of concern (VOC). Data on kinetics, activation- and equilibrium thermodynamics of binding of the receptor binding domain (RBD) from VOC with ACE2 as well as data from computational protein electrostatics revealed a profound remodeling of the physicochemical characteristics of the interaction during the evolution. Thus, as compared to RBDs from Wuhan strain and other VOC, Omicron RBD presented as a unique protein in terms of conformational dynamics and types of non-covalent forces driving the complex formation with ACE2. Viral evolution resulted in a restriction of the RBD structural dynamics, and a shift to a major role of electrostatic forces for ACE2 binding. Further, we investigated how the reshaping of the physicochemical qualities affect the functional properties of S proteins. Data from various binding assays revealed that SARS-CoV-2 Wuhan and Omicron RBDs manifest capacity for off-target (promiscuous) recognition of multiple unrelated proteins, but they harbor distinct reactivity patterns. This study provides mechanistic explanations for changes in the viral tropism, infectivity, and capacity to evade immune responses during evolution. Competing Interest Statement The authors have declared no competing interest. Footnotes * Interpretation of thermodynamic data as well as display of Figure 5E.