Study Of Evaluate Interactions Between SARS-CoV-2 RBD And Full-length ACE2 With Coarse-grained Molecular Dynamics Simulations

Since the emergence of severe acute respiratory syndrome coronavirus 2(SARS-Co V-2)in late 2019,it has rapidly spread all over the world,posing great challenges to human survival and normal life.Compared with SARS-Co V,which caused severe acute respiratory syndrome in 2003,the receptor-binding domain(RBD)of SARS-Co V-2 reduces the emerging frequency of its active conformation to escape human immune surveillance,while increasing its ability to bind to angiotensin-converting enzyme 2(ACE2),the receptor of human cell surfaces.Which makes it as infectious as SARS-Co V,but more difficult to detect and clear by the immune system.Therefore,the detailed analysis of the binding effect between SARS-Co V-2 and ACE2 has important scientific significance.In recent years,with the greatly improved computing power and the successes in the combinations between molecular simulations and experiments,molecular simulation has become a powerful tool to study protein-protein interactions.In this paper,a coarse-grained model,which is more advantageous in size and time scale than the allatom model,and is more suitable for studying biological macromolecular systems,was chosen to construct the simulation system.Multiple μs-scale MARTINI coarse-grained molecular dynamics simulations were performed to reveal the details of the interaction between the SARSCo V-2 RBD and full-length human ACE2.The research contents are summarized as follows:(1)Key amino acid pairs that mediate the binding of the ACE2 peptidase domain(PD)by the SARS-CoV-2 RBD.Within our simulation duration of 1.2 μs,the residue pairs on the binding interface of SARS-CoV-2 RBD and ACE2 PD changed dynamically,but formed a stable pincer-like structure.The amino acid residues on the pincer structure all occur with a high frequency.F486 on the SARS-CoV-2 RBD forms one end of the plier and is anchored in a hydrophobic pocket,consisting of F28,L79 and Y83 at the end of the ACE2 PD.Y505 and Q498 on the RBD form another end of the plier and are responsible for binding to residues at the junction of the β3 andβ4 sheets and the middle hydrophobic region of the α1-helix on ACE2 PD.In a flexible and dynamic pattern,the amino acids between the two ends of the plier interacts bind to the corresponding region on ACE2 PD,which makes the binding of SARS-CoV-2 RBD to ACE2 PD with unpredictability.From the perspective of spatial structure,the ACE2 PD side of binding interface is a relatively rigid domain containing multiple secondary structures,especially the α1-helix andα2-helix at the N-terminus of ACE2;while the SARS-CoV-2 RBD side of binding interface is composed of several β-sheets followed by a flexible region,receptor-binding motif(RBM),similar to the gecko’s sucker tentacles.The interface composed of rigid and flexible structures makes the binding between SARS-CoV-2 RBD and ACE2 PD very stable,and the presence of RBM improves the possibility of binding to ACE2 PD and provides greater binding affinity.(2)The absence of B0AT1 increases the propensity of the ACE2 to approach the membrane.By controlling the number of SARS-CoV-2 RBDs in the system and the presence or absence of the neutral amino acid transporter B0AT1,we found that the absence of B0AT1 significantly increases the probability of ACE2 approaching the membrane,especially for the ACE2 PD.Moreover,in the system without B0AT1,as the number of RBDs increases,a transition region with a gradually increasing area will appear in the two-dimensional Gibbs free energy diagram,indicating that the process of ACE2 PD approaching the POPC membrane has an intermediate conformation,which is more consistent with General physical processes.The above results suggest that the neutral amino acid transporter B0AT1 may play a crucial role in the process of SARS-Co V-2 approaching the membrane,which can be used as a new idea for drug development.