Molecular Dynamics Analysis of Fast-Spreading Severe Acute Respiratory Syndrome Coronavirus 2 Variants and Their Effects on the Interaction with Human Angiotensin-Converting Enzyme 2

Author(s):Show less -

de Souza, Anacleto Silva ; Amorim, Vitor Martins de Freitas ; Guardia, Gabriela D. A. ; dos Santos, Felipe R. C. ; dos Santos, Filipe F. ; de Souza, Robson Francisco ; Juvenal, Guilherme de Araujo ; Huang, Yihua ; Ge, Pingju ; Jiang, Yinan ; Li, Coco ; Paudel, Prajwal ; Ulrich, Henning ; Galante, Pedro A. F. ; Guzzo, Cristiane Rodrigues

• Document type: Journal article
• Source: ACS OMEGA; v. 7, n. 35, p. 10-pg., 2022-08-24.

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is evolving with mutations in the spike protein, especially in the receptor-binding domain (RBD). The failure of public health measures in some countries to contain the spread of the disease has given rise to novel viral variants with increased transmissibility. However, key questions about how quickly the variants can spread remain unclear. Herein, we performed a structural investigation using molecular dynamics simulations and determined dissociation constant (KD) values using surface plasmon resonance assays of three fast-spreading SARS-CoV-2 variants, alpha, beta, and gamma, as well as genetic factors in host cells that may be related to the viral infection. Our results suggest that the SARS-CoV-2 variants facilitate their entry into the host cell by moderately increased binding affinities to the human ACE2 receptor, different torsions in hACE2 mediated by RBD variants, and an increased spike exposure time to proteolytic enzymes. We also found that other host cell aspects, such as gene and isoform expression of key genes for the infection (ACE2, FURIN, and TMPRSS2), may have few contributions to the SARS-CoV-2 variant infectivity. In summary, we concluded that a combination of viral and host cell factors allows SARS-CoV-2 variants to increase their abilities to spread faster than the wild type. (AU)

• FAPESP's process: 20/06091-1 - Analyses of genetic variants determining the infection and evolution course of COVID-19 in young adults
• Grantee: Pedro Alexandre Favoretto Galante
• Support Opportunities: Regular Research Grants
• FAPESP's process: 17/18246-7 - Overlapped genes: mutual regulation of coding and noncoding genes biogenesis
• Grantee: Felipe Rodolfo Camargo dos Santos
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)
• FAPESP's process: 17/19541-2 - Impact of RNA binding proteins on abnormal regulation of splicing in glioblastoma
• Grantee: Gabriela Der Agopian Guardia
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• FAPESP's process: 20/04680-0 - Design of different fragments of SARS-CoV-2 surface protein spike for the development of fast diagnostic test and vaccine
• Grantee: Cristiane Rodrigues Guzzo Carvalho
• Support Opportunities: Regular Research Grants
• FAPESP's process: 19/00195-2 - Understanding the c-di-GMP signaling networks and the Type II secretion system present into the human pathogen Leptospira interrogans Copenhageni
• Grantee: Cristiane Rodrigues Guzzo Carvalho
• Support Opportunities: Regular Research Grants
• FAPESP's process: 16/09047-8 - Comparative genomics of bacterial toxins associated with type IV secretion systems
• Grantee: Robson Francisco de Souza
• Support Opportunities: Regular Research Grants
• FAPESP's process: 18/15579-8 - Retroelements: a driving force generating genetic novelties in the human and mouse genome
• Grantee: Pedro Alexandre Favoretto Galante
• Support Opportunities: Research Grants - Young Investigators Grants - Phase 2
• FAPESP's process: 18/07366-4 - Purine and kinin receptors as targets of study and therapeutic interventions in neurological diseases
• Grantee: Alexander Henning Ulrich
• Support Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 20/14158-9 - Identification of alternative membrane protein isoforms as potential biomarkers for tumors with poor prognosis and scarce therapeutic options
• Grantee: Filipe Ferreira dos Santos
• Support Opportunities: Scholarships in Brazil - Doctorate