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Exploring the role of framework mutations in enabling breadth of a cross-reactive antibody (CR3022) against the SARS-CoV-2 RBD and its variants of concern.
Saini, Samvedna; Agarwal, Manusmriti; Pradhan, Amartya; Pareek, Savitha; Singh, Ashish K; Dhawan, Gagan; Dhawan, Uma; Kumar, Yatender.
  • Saini S; Department of Biological Sciences and Engineering, Netaji Subhas University of Technology, New Delhi, India.
  • Agarwal M; Department of Biological Sciences and Engineering, Netaji Subhas University of Technology, New Delhi, India.
  • Pradhan A; Faculty of Technology, University of Delhi, New Delhi, India.
  • Pareek S; Department of Biological Sciences and Engineering, Netaji Subhas University of Technology, New Delhi, India.
  • Singh AK; Faculty of Technology, University of Delhi, New Delhi, India.
  • Dhawan G; Department of Biological Sciences, Tata Institute of Fundamental Research, Mumbai, India.
  • Dhawan U; High Performance Computing (HPC) & AI Innovation Lab, Dell EMC, Bengaluru, India.
  • Kumar Y; High Performance Computing (HPC) & AI Innovation Lab, Dell EMC, Bengaluru, India.
J Biomol Struct Dyn ; : 1-14, 2022 Jan 31.
Article in English | MEDLINE | ID: covidwho-2279351
ABSTRACT
Cross-reactive and broadly neutralizing antibodies against surface proteins of diverse strains of rapidly evolving viral pathogens like SARS-CoV-2 can prevent infection and therefore are crucial for the development of effective universal vaccines. While antibodies typically incorporate mutations in their complementarity determining regions during affinity maturation, mutations in the framework regions have been reported as players in determining properties of broadly neutralizing antibodies against HIV and the Influenza virus. We propose an increase in the cross-reactive potential of CR3022 against the emerging SARS- CoV-2 variants of concern through enhanced conformational flexibility. In this study, we use molecular dynamics simulations, in silico mutagenesis, structural modeling, and docking to explore the role of light chain FWR mutations in CR3022, a SARS-CoV anti-spike (S)-protein antibody cross-reactive to the S-protein receptor binding domain of SARS-CoV-2. Our study shows that single substitutions in the light chain framework region of CR3022 with conserved epitopes across SARS-CoV strains allow targeting of diverse antibody epitope footprints that align with the epitopes of recently-categorized neutralizing antibody classes while enabling binding to more than one strain of SARS-CoV-2. Our study has implications for rapid and evolution-based engineering of broadly neutralizing antibodies and reaffirms the role of framework mutations in effective change of antibody orientation and conformation via improved flexibility.Communicated by Ramaswamy H. Sarma.
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Full text: Available Collection: International databases Database: MEDLINE Type of study: Randomized controlled trials Topics: Vaccines / Variants Language: English Journal: J Biomol Struct Dyn Year: 2022 Document Type: Article Affiliation country: 07391102.2022.2030800

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Full text: Available Collection: International databases Database: MEDLINE Type of study: Randomized controlled trials Topics: Vaccines / Variants Language: English Journal: J Biomol Struct Dyn Year: 2022 Document Type: Article Affiliation country: 07391102.2022.2030800