Dynamics of the ACE2 - SARS-CoV/SARS-CoV-2 spike protein interface reveal unique mechanisms

Abstract

The coronavirus disease 2019 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 all atom molecular dynamics simulations of at least 500 ns each were performed to better understand the structural stability and interfacial interactions between the receptor binding domain of the spike 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 and SARS-CoV-2 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 spike 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 SARS-CoV-ACE2 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. 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.

Critical Interactions Between the SARS-CoV-2 Spike Glycoprotein and the Human ACE2 Receptor

“…More recent studies used the crystal structure of SARS-CoV-2 RBD in complex with ACE2 to perform coarse-grained 19 and all-atom 20,21,22,23 MD simulations. The effect of the mutations that disrupt close contact residues between SARS-CoV-2 RBD and ACE2 on binding free energy was investigated by post-processing of the MD trajectories 15,16,21,22 or by using bioinformatic methods 20 . The work required to unbind the S protein from ACE2 would provide a more accurate estimate of the binding strength, but this has not been performed under low pulling velocities using the structure of SARS-CoV-2 RBD in complex with ACE2.…”

Modelling conformational state dynamics and its role on infection for SARS-CoV-2 Spike protein variants

“…Such integration permits to speed up research, decrease needs in infrastructure, reagents, and human resources and allows us to evaluate increasingly larger data sets. Computational approaches are being extensively used in the study of SARS-CoV-2 and its mechanisms of infection [13][14][15]. Among these, we highlight the study of dynamic properties of the Spike protein as well as in antibody recognition and the search for therapeutic interventions [16][17][18].…”

Small Molecules to Destabilize the ACE2-RBD Complex: A Molecular Dynamics Study for Potential COVID-19 Therapeutics

“…The best docking pose has a score of -8.04 kcal/mol which is close to the case of Nilotinib with the score -8.34 kcal/mol. Our docking results show that both Nilotinib and SSAA09E2 can potentially interfere with some of the important ACE2-RBD interactions such as Tyr449-Asp38, Tyr453-His34, and Gln493-Glu35 (1,2,36,37). To analyze the stability and conformational changes of protein structures, 200 ns of MD simulation is performed for the control group without drugs, and ACE2-RBD complexes bound with Nilotinib and SSAA09E2, respectively.…”