Molecular Dynamics Study Of SARS-CoV-2 Binding To Receptor ACE2 And Zeolite Surface

Since the outbreak of SARS-CoV-2 in 2019,it has rapidly spread to various countries and regions,causing huge damage to the normal functioning of society.Significant infectivity and lethality urgently require us to understand and grasp the infection/transmission behavior of SARS-CoV-2 at the molecular level.SARS-CoV-2 and SARS-CoV are very closely related,and the key steps in their invasion of human cells are the binding of the receptor binding domain(RBD)on the S protein and the human receptor ACE2,but many in vitro binding studies have shown that the binding affinity of SARS-CoV-2-RBD to ACE2 is about 20 times higher than that of SARSCoV,and it is necessary to explore the reasons for this difference.As a porous aluminosilicate material,zeolite also plays an important role in the field of biomedicine.Metal cation exchange is the most convenient and easy-to-replicate method for zeolite modification.It can control the properties of the zeolite surface by utilizing the ion exchange properties of the zeolite negatively charged framework to achieve the effect of selective adsorption of specific proteins.At present,experimental work has found that copper ion-exchanged zeolite has excellent neutralization effect on SARS-CoV-2.However,limited by experimental methods,there is still a lack of intuitive and powerful explanations for this specific neutralization.In this paper,molecular dynamics simulation,steered molecular dynamics simulation and umbrella sampling methods were used to study the dynamic process of the binding and unbinding between RBD of SARS-COV-2 and SARS-CoV and ACE2,focusing on revealing the characteristics of SARS-CoV-2-RBD from the perspective of binding free energy.The effect of residues sequence changes on structure and ACE2 binding affinity was discussed.Then,the adsorption kinetics of SARS-CoV-2-RBD on the surface of Y zeolite exchanged with four metal cations(Na+,Cu2+,Zn2+ and Ca2+)was studied.The neutralization mechanism of Cu2+ exchanged zeolite on RBD was explored at atomic scale,and the unique role of Cu2+ in RBD was explained.The main conclusions of this paper are as follows:1.The difference between SARS-CoV-2-RBD and SARS-CoV-RBD residues eventually resulted in the difference in contact residues.The β-loop region of SARS-CoV-RBD is highly flexible.Although it can maintain long-term adhesion with ACE2 during unbinding process,there is no significant interaction when it enters the stable binding state.However,the β-loop region of SARS-CoV-2-RBD changes its secondary structure due to the difference of residues sequence.The stable β-sheet supports the conformational stability of β-loop region,which provides additional key residues and stronger interactions with ACE2.The binding free energies of SARS-CoV-2-RBD/ACE2 and SARS-CoV-RBD/ACE2 calculated in this paper were about-110.0 kJ·mol-1 and-101.2 kJ·mol-1,respectively,which showed a 30-fold affinity difference basically consistent with the experimental results.This fully explains the high infectivity of SARS-COV-2.2.The adsorption of RBD by Y zeolites is characterized by one side of the β1 sheet as the dominant orientation,but only the Cu2+ exchanged CuNaY zeolites can specifically bind to RBD.The adsorption of RBD by Cu2+ exchanged zeolites shows synergism between zeolites and Cu2+,while the other zeolites do not.Due to the excellent cation exchange properties of negatively charged framework of zeolite,the surface of CuNaY zeolite can anchor two very close Cu2+,forming a chain-type coordination with the two oxygen atoms of Glu340 side chain carboxylate,similar to that in biology.In addition,Glu340 and Lys356,which are very close in space,can mutually promote the binding with zeolite as a whole,and the system of ZnNaY zeolite binding to RBD also inspires us to enhance the binding of RBD by artificially creating defects on the surface of zeolite.