Anchor-Locker Binding Mechanism of the Coronavirus Spike Protein to Human ACE2: Insights from Computational Analysis

Abstract

COVID-19 has emerged as the most serious international pandemic in early 2020 and the lack of comprehensive knowledge in the recognition and transmission mechanisms of this virus hinders the development of suitable therapeutic strategies. The specific recognition during the binding of the spike glycoprotein (S protein) of coronavirus to the angiotensin-converting enzyme 2 (ACE2) in the host cell is widely considered the first step of infection. However, detailed insights on the underlying mechanism of dynamic recognition and binding of these two proteins remain unknown. In this work, molecular dynamics simulation and binding free energy calculation were carried out to systematically compare and analyze the receptor-binding domain (RBD) of six coronavirus’ S proteins. We found that affinity and stability of the RBD from SARS-CoV-2 under the binding state with ACE2 are stronger than those of other coronaviruses. The solvent-accessible surface area (SASA) and binding free energy of different RBD subunits indicate an “anchor-locker” recognition mechanism involved in the binding of the S protein to ACE2. Loop 2 (Y473-F490) acts as an anchor for ACE2 recognition, and Loop 3 (G496-V503) locks ACE2 at the other nonanchoring end. Then, the charged or long-chain residues in the β-sheet 1 (N450-F456) region reinforce this binding. The proposed binding mechanism was supported by umbrella sampling simulation of the dissociation process. The current computational study provides important theoretical insights for the development of new vaccines against SARS-CoV-2.

Waves and variants of SARS-CoV-2: understanding the causes and effect of the COVID-19 catastrophe

“…β-sheet 1 is involved in enhancing the binding after the recognition process. These interactions reinforce the binding between the spike protein of the SARS-CoV-2 and the ACE-2 of the host cell [ 22 ].…”

“…The Epsilon (GH/452R.V1) variant first identified in California, the USA in 2021, showed a 20% increase in transmission possibly attributed to the L452R and D614G substitutions in the spike protein [36]. As of 13th July 2021, cases of Epsilon variant have been reported from 34 nations dominantly in the USA (52,967), Mexico (477), Canada (331), South Korea (109), Aruba (58), Denmark (36), Chile (30), Argentina (28), UK (22), Australia (20), and Colombia (20) (Fig. 5 A) [37].…”

“…As of 13th July 2021, more than 160 countries reported the presence of Alpha variant cases, i.e. UK (266,186), USA (201,074), Germany (101,697), Denmark (59,844), Sweden (56,325), France (32,208), Netherlands (27,660), Italy (24,075), Japan (22,382), and Switzerland (21,628) (Fig. 7A), suggesting community transmission and hospitalization [37].…”

Structure-guided glyco-engineering of ACE2 for improved potency as soluble SARS-CoV-2 decoy receptor

“…26 Other MD studies concluded that the glycans attached to N90 and N322 of ACE2 could be major determinants of Spike binding, 25 while yet other simulation works postulate that glycosylation does not affect the RBD-ACE2 interaction significantly. 27,28 Genetic or pharmacological blockade of N-glycan biosynthesis at the oligomannose stage in ACE2expressing target cells was found to dramatically reduce viral entry, 29 even though several glycoforms of ACE2 were found to display comparatively moderate variation with respect to Spike binding. 30 Hence, a detailed understanding on how individual glycans on both Spike and ACE2 influence their interaction and a comprehensive experimental validation of the MD findings is crucial for the rational design of novel therapeutic soluble ACE2 variants with enhanced Spike binding affinity and the capacity to block viral entry more efficiently than the native enzyme.…”

Structure-guided glyco-engineering of ACE2 for improved potency as soluble SARS-CoV-2 decoy receptor

“…26 Other MD studies concluded that the glycans attached to N90 and N322 of ACE2 could be major determinants of Spike binding, 25 while yet other simulation works postulate that glycosylation does not affect the RBD-ACE2 interaction significantly. 27,28 Genetic or pharmacological blockade of N-glycan biosynthesis at the oligomannose stage in ACE2-expressing target cells was found to dramatically reduce viral entry, 29 even though several glycoforms of ACE2 were found to display comparatively moderate variation with respect to Spike binding. 30 Hence, a detailed understanding on how individual glycans on both Spike and ACE2 influence their interaction and a comprehensive experimental validation of the MD findings is crucial for the rational design of novel therapeutic soluble ACE2 variants with enhanced Spike binding affinity and the capacity to block viral entry more efficiently than the native enzyme.…”