Abstract
The coronavirus disease 2019 (COVID-19) pandemic, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a major public health concern. A handful of static structures now provide molecular insights into how SARS-CoV-2 and SARS-CoV interact with its host target, which is the angiotensin converting enzyme 2 (ACE2). Molecular recognition, binding and function are dynamic processes. To evaluate this, multiple 500 ns or 1 μs all-atom molecular dynamics simulations were performed to better understand the structural stability and interfacial interactions between the receptor binding domain of the spike (S) protein of SARS-CoV-2 and SARS-CoV bound to ACE2. Several contacts were observed to form, break and reform in the interface during the simulations. Our results indicate that SARS-CoV-2 and SARS-CoV utilizes unique strategies to achieve stable binding to ACE2. Several differences were observed between the residues of SARS-CoV-2 and SARS-CoV that consistently interacted with ACE2. Notably, a stable salt bridge between Lys417 of SARS-CoV-2 S protein and Asp30 of ACE2 as well as three stable hydrogen bonds between Tyr449, Gln493 and Gln498 of SARS-CoV-2 and Asp38, Glu35 and Lys353 of ACE2 were observed, which were absent in the ACE2–SARS-CoV interface. Some previously reported residues, which were suggested to enhance the binding affinity of SARS-CoV-2, were not observed to form stable interactions in these simulations. Molecular mechanics-generalized Born surface area based free energy of binding was observed to be higher for SARS-CoV-2 in all simulations. Stable binding to the host receptor is crucial for virus entry. Therefore, special consideration should be given to these stable interactions while designing potential drugs and treatment modalities to target or disrupt this interface.
Highlights
The recent outbreak of coronavirus disease 2019 (COVID-19), caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has affected all walks of life
Five hundred nanosecond molecular dynamics (MD) simulations of two angiotensin converting enzyme 2 (ACE2)–SARS-CoV-2 structures (PDB IDs: 6M0J and 6LZG) were performed in triplicate to ensure that results were not biased by a single structure
This study provides insight into the stability of the interactions that define the ACE2–SARS-CoV-2 and ACE2–SARS-CoV interfaces, using extended MD simulations of multiple structures of these complexes
Summary
The recent outbreak of coronavirus disease 2019 (COVID-19), caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has affected all walks of life. Genomic studies have established that SARS-CoV-2 belong to the betacoronavirus genus, which includes SARS-CoV and MERS-CoV that were associated with previous outbreaks of relatively smaller scale[1,2,3]. These coronaviruses attach to the host cell with the aid of the spike (S) glycoprotein present on its envelope. SARS-CoV-2 residues Gln[493] and Asn[501] (Asn[479] and Thr[487] in SARSCoV) are located near viral binding hotspot residues Lys[31] and Lys[353] on human ACE2. The mutated residues interact more favourably with the viral hotspot residues and contribute more to the binding of SARS-CoV-2 to ACE2 when compared to SARS-CoV7,11. The stability of these interactions have not been clearly elucidated
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