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Structural analysis of ACE2 variant N720D demonstrates a higher binding affinity to TMPRSS2.

ABSTRACT: AIMS:Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a novel member of the betacoronaviruses family affecting the lower respiratory tract mainly through binding to angiotensin converting enzyme 2 (ACE2) via its S-protein. Genetic analysis of (ACE2) gene revealed several variants that have been suggested to regulate the interaction with S protein. This study investigates the N720D variant, positioned in the collectrin-like domain (CLD) at proximity to type II transmembrane serine protease (TMPRSS2) cleavage site. MAIN METHODS:The effect of N720D variant on ACE2 structure and thermodynamic stability was studied by DynaMut. HDOCK was utilised to model TMPRSS2 protease binding to ACE2 WT and D720 variant cleavage site. PRODIGY was used to calculate binding affinities and MD simulation tools calculated the at 100 ns for ACE2 apo structure and the ACE2-TMPRSS2 complex. KEY FINDINGS:The N720D variant is a more dynamic structure with a free energy change (??G): -0.470 kcal/mol. As such, introducing a tighter binding affinity of Kd = 3.2 × 10-10 M between TMPRSS2 and N720D variant. RMSD, RMSF calculations showed the N720D variant is less stable, however, RMSF values of the D720-TMPRSS2 complex reflected a slower dynamic motion. SIGNIFICANCE:The hotspot N720D variant in the CLD of ACE2 affected the stability and flexibility of ACE2 by increasing the level of motion in the loop region, resulting in a more favourable site for TMPRSS2 binding and cleavage. Consequently, this would facilitate S-protein binding and can potentially increase viral entry highlighting the importance of variants affecting the ACE2-TMPRSS2 complex.

SUBMITTER: Mohammad A

PROVIDER: S-EPMC7405906 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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Structural analysis of ACE2 variant N720D demonstrates a higher binding affinity to TMPRSS2.

Mohammad Anwar A Marafie Sulaiman K SK Alshawaf Eman E Abu-Farha Mohamed M Abubaker Jehad J Al-Mulla Fahd F

Life sciences 20200805

<h4>Aims</h4>Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a novel member of the betacoronaviruses family affecting the lower respiratory tract mainly through binding to angiotensin converting enzyme 2 (ACE2) via its S-protein. Genetic analysis of (ACE2) gene revealed several variants that have been suggested to regulate the interaction with S protein. This study investigates the N720D variant, positioned in the collectrin-like domain (CLD) at proximity to type II transmembrane s ...[more]

PMID: 32768580

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Project description:Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), the causative agent of COVID -19, is constantly evolving, requiring continuous genomic surveillance. In this study, we used whole-genome sequencing to investigate the genetic epidemiology of SARS-CoV-2 in Bangladesh, with particular emphasis on identifying dominant variants and associated mutations. We used high-throughput next-generation sequencing (NGS) to obtain DNA sequences from COVID-19 patient samples and compared these sequences to the Wuhan SARS-CoV-2 reference genome using the Global Initiative for Sharing All Influenza Data (GISAID). Our phylogenetic and mutational analyzes revealed that the majority (88%) of the samples belonged to the pangolin lineage B.1.1.25, whereas the remaining 11% were assigned to the parental lineage B.1.1. Two main mutations, D614G and P681R, were identified in the spike protein sequences of the samples. The D614G mutation, which is the most common, decreases S1 domain flexibility, whereas the P681R mutation may increase the severity of viral infections by increasing the binding affinity between the spike protein and the ACE2 receptor. We employed molecular modeling techniques, including protein modeling, molecular docking, and quantum mechanics/molecular mechanics (QM/MM) geometry optimization, to build and validate three-dimensional models of the S_D614G-ACE2 and S_P681R-ACE2 complexes from the predominant strains. The description of the binding mode and intermolecular contacts of the referenced systems suggests that the P681R mutation may be associated with increased viral pathogenicity in Bangladeshi patients due to enhanced electrostatic interactions between the mutant spike protein and the human ACE2 receptor, underscoring the importance of continuous genomic surveillance in the fight against COVID -19. Finally, the binding profile of the S_D614G-ACE2 and S_P681R-ACE2 complexes offer valuable insights to deeply understand the binding site characteristics that could help to develop antiviral therapeutics that inhibit protein-protein interactions between SARS-CoV-2 spike protein and human ACE2 receptor.

Project description:There is enormous ongoing interest in characterizing the binding properties of the SARS-CoV-2 Omicron Variant of Concern (VOC) (B.1.1.529), which continues to spread towards potential dominance worldwide. To aid these studies, based on the wealth of available structural information about several SARS-CoV-2 variants in the Protein Data Bank (PDB) and a modeling pipeline we have previously developed for tracking the ongoing global evolution of SARS-CoV-2 proteins, we provide a set of computed structural models (henceforth models) of the Omicron VOC receptor-binding domain (omRBD) bound to its corresponding receptor Angiotensin-Converting Enzyme (ACE2) and a variety of therapeutic entities, including neutralizing and therapeutic antibodies targeting previously-detected viral strains. We generated bound omRBD models using both experimentally-determined structures in the PDB as well as machine learningbased structure predictions as starting points. Examination of ACE2-bound omRBD models reveals an interdigitated multi-residue interaction network formed by omRBD-specific substituted residues (R493, S496, Y501, R498) and ACE2 residues at the interface, which was not present in the original Wuhan-Hu-1 RBD-ACE2 complex. Emergence of this interaction network suggests optimization of a key region of the binding interface, and positive cooperativity among various sites of residue substitutions in omRBD mediating ACE2 binding. Examination of neutralizing antibody complexes for Barnes Class 1 and Class 2 antibodies modeled with omRBD highlights an overall loss of interfacial interactions (with gain of new interactions in rare cases) mediated by substituted residues. Many of these substitutions have previously been found to independently dampen or even ablate antibody binding, and perhaps mediate antibody-mediated neutralization escape ( e.g ., K417N). We observe little compensation of corresponding interaction loss at interfaces when potential escape substitutions occur in combination. A few selected antibodies ( e.g ., Barnes Class 3 S309), however, feature largely unaltered or modestly affected protein-protein interfaces. While we stress that only qualitative insights can be obtained directly from our models at this time, we anticipate that they can provide starting points for more detailed and quantitative computational characterization, and, if needed, redesign of monoclonal antibodies for targeting the Omicron VOC Spike protein. In the broader context, the computational pipeline we developed provides a framework for rapidly and efficiently generating retrospective and prospective models for other novel variants of SARS-CoV-2 bound to entities of virological and therapeutic interest, in the setting of a global pandemic.

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Structural analysis of ACE2 variant N720D demonstrates a higher binding affinity to TMPRSS2.

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Structural analysis of ACE2 variant N720D demonstrates a higher binding affinity to TMPRSS2.

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