An Integrated Understanding of the Evolutionary and Structural Features of the SARS-CoV-2 Spike Receptor Binding Domain (RBD)
Document Type
Article
Publication Date
2022
Keywords
Covid-19, Sars-cov-2, Receptor Binding Domain, Sequence Space Analysis, Co-evolution, Deep Mutation Scan, Molecular Dynamic Simulation, Structure Network Analysis, Fuzzy C-means Clustering, Druggability, Machine Learning
Digital Object Identifier (DOI)
International Journal of Biological Macromolecules
Abstract
Conventional drug development strategies typically use pocket in protein structures as drug-target sites. They overlook the plausible effects of protein evolvability and resistant mutations on protein structure which in turn may impair protein-drug interaction. In this study, we used an integrated evolution and structure guided strategy to develop potential evolutionary-escape resistant therapeutics using receptor binding domain (RBD) of SARS-CoV-2 spike-protein/S-protein as a model. Deploying an ensemble of sequence space exploratory tools including co-evolutionary analysis and deep mutational scans we provide a quantitative insight into the evolutionarily constrained subspace of the RBD sequence-space. Guided by molecular simulation and structure network analysis we highlight regions inside the RBD, which are critical for providing structural integrity and conformational flexibility. Using fuzzy C-means clustering we combined evolutionary and structural features of RBD and identified a critical region. Subsequently, we used computational drug screening using a library of 1615 small molecules and identified one lead molecule, which is expected to target the identified region, critical for evolvability and structural stability of RBD. This integrated evolution-structure guided strategy to develop evolutionary-escape resistant lead molecules have potential general applications beyond SARS-CoV-2.
Was this content written or created while at USF?
Yes
Citation / Publisher Attribution
International Journal of Biological Macromolecules, v. 217, p. 492-505
Scholar Commons Citation
Sanyal, Dwipanjan; Banerjee, Suharto; Bej, Aritra; Chowdhury, Vaidehi Roy; Uversky, Vladimir N.; Chowdhury, Sourav; and Chattopadhyay, Krishnananda, "An Integrated Understanding of the Evolutionary and Structural Features of the SARS-CoV-2 Spike Receptor Binding Domain (RBD)" (2022). Molecular Medicine Faculty Publications. 955.
https://digitalcommons.usf.edu/mme_facpub/955
