Spike Proteins of SARS-CoV and SARS-CoV-2 Utilize Different Mechanisms to Bind With Human ACE2

Xie, Yixin; Karki, Chitra B.; Du, Dan; Li, Haotian; Wang, Jun; Sobitan, Adebiyi; Teng, Shaolei; Tang, Qiyi; Li, Lin

doi:10.3389/fmolb.2020.591873

Cited by 93 publications

(95 citation statements)

References 53 publications

(68 reference statements)

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“…Although the SARS-CoV-2 preserves almost 70% of the sequence of the previous SARS-CoV virus, the differences are enough to affect the pathogenicity. Several studies show that the SARS-CoV-2 has a higher binding affinity with its host-cell receptor, angiotensin-converting enzyme 2 (ACE2) (1)(2)(3)(4). The higher risk of virus initial recognition can justify the higher infectivity of the novel coronavirus.…”

Section: Introductionmentioning

confidence: 99%

Small molecule therapeutics to destabilize the ACE2-RBD complex: A molecular dynamics study

Razizadeh

Nikfar

Liu

2021

Biophysical Journal

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The ongoing COVID-19 pandemic has infected millions of people, claimed hundreds of thousands of lives, and made a worldwide health emergency. Understanding the SARS-CoV-2 mechanism of infection is crucial in the development of potential therapeutics and vaccines. The infection process is triggered by direct binding of the SARS-CoV-2 receptor-binding domain (RBD) to the host cell receptor, angiotensin-converting enzyme 2 (ACE2). Many efforts have been made to design or repurpose therapeutics to deactivate the RBD or ACE2 and prevent the initial binding. In addition to direct inhibition strategies, small chemical compounds might be able to interfere and destabilize the meta-stable, pre-fusion complex of ACE2-RBD. This approach can be employed to prevent the further progress of virus infection at its early stages. In this study, molecular docking was employed to analyze the binding of two chemical compounds, SSAA09E2 and Nilotinib, with the druggable pocket of the ACE2-RBD complex. The structural changes as a result of the interference with the ACE2-RBD complex were analyzed by molecular dynamics simulations. Results show that both Nilotinib and SSAA09E2 can induce significant conformational changes in the ACE2-RBD complex, intervene with the hydrogen bonds, and influence the flexibility of proteins. Moreover, essential dynamics analysis suggests that the presence of small molecules can trigger large-scale conformational changes that may destabilize the ACE2-RBD complex.

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Section: Introductionmentioning

confidence: 99%

Small molecule therapeutics to destabilize the ACE2-RBD complex: A molecular dynamics study

Razizadeh

Nikfar

Liu

2021

Biophysical Journal

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“…SARS-CoV-2 possesses a higher electric field line density when compared to SARS-CoV, thus there is obviously a stronger interaction between SARS-CoV-2 and ACE2 when compared to that of SARS-CoV. The latter fact may be the major reason behind the fast-spreading of SARS-CoV-2 as compared to SARS-CoV [ 50 – 52 ].…”

Section: Pathogenesis Of Covid-19mentioning

confidence: 99%

Understanding the role of ACE-2 receptor in pathogenesis of COVID-19 disease: a potential approach for therapeutic intervention

et al. 2021

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Angiotensin-converting enzyme (ACE) and its homologue, ACE2, are commonly allied with hypertension, renin–angiotensin–aldosterone system pathway, and other cardiovascular system disorders. The recent pandemic of COVID-19 has attracted the attention of numerous researchers on ACE2 receptors, where the causative viral particle, SARS-CoV-2, is established to exploit these receptors for permitting their entry into the human cells. Therefore, studies on the molecular origin and pathophysiology of the cell response in correlation to the role of ACE2 receptors to these viruses are bringing novel theories. The varying level of manifestation and importance of ACE proteins, underlying irregularities and disorders, intake of specific medications, and persistence of assured genomic variants at the ACE genes are potential questions raising nowadays while observing the marked alteration in response to the SARS-CoV-2-infected patients. Therefore, the present review has focused on several raised opinions associated with the role of the ACE2 receptor and its impact on COVID-19 pathogenesis.

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“…We speculate that the calculated dielectric constants of the Spike-protein can be helpful in their design and implementation. On other hand, the electrostatic interactions have been demonstrated to play a major role in enhancing the binding affinity of RBD of SARS-CoV-2 to ACE2 as compared to SARS-CoV [69][70][71][72] and the polar solvation free energy of RBD-ACE2 complex is in fact quite sensitive to the electronic dielectric constant. However, all these MD simulations are based on the continuum models with uncertain dielectric constants for RBD or ACE2, that are usually assumed in the range of 1 to 4.…”

Section: Specific Applicationsmentioning

confidence: 99%

Ab Initio Electronic Dielectric “Constant” of Proteins: A Baseline for Electrostatic Interaction in Biomolecular Systems

Adhikari¹,

Podgornik²,

Jawad³

et al. 2021

Preprint

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The protein dielectric constant reflects the molecular heterogeneity of the proteins and can be decomposed into different components depending on the size, structure, composition, locality, and environment of the protein in general. The long history of its computation and measurement attest to the vital importance of electrostatic interactions in protein physics that engendered diverse theoretical approaches based often on scattered methodologies with various adjustable parameters. We present a new robust computational method anchored in rigorous ab initio quantum mechanical calculation of explicit atomistic models, without any indeterminate parameters to compute and gain insight into the electronic component of the static dielectric constants of small proteins under different conditions. We implement the new methodology to the 20 canonical amino acids individually, a polypeptide RGD-4C (1FUV) in different environments, and the SD1 domain in the Spike protein of SARS-COV-2. The calculated electronic dielectric constants for 1FUV and SD1 in vacuum are 28.06 and 50.02 respectively. They decrease in the presence of aqueous bathing solution.

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Spike Proteins of SARS-CoV and SARS-CoV-2 Utilize Different Mechanisms to Bind With Human ACE2

Cited by 93 publications

References 53 publications

Small molecule therapeutics to destabilize the ACE2-RBD complex: A molecular dynamics study

Small molecule therapeutics to destabilize the ACE2-RBD complex: A molecular dynamics study

Understanding the role of ACE-2 receptor in pathogenesis of COVID-19 disease: a potential approach for therapeutic intervention

Ab Initio Electronic Dielectric “Constant” of Proteins: A Baseline for Electrostatic Interaction in Biomolecular Systems

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