A graph-based approach identifies dynamic H-bond communication networks in spike protein S of SARS-CoV-2

• Published in: Journal of structural biology 2020-11, Vol.212 (2), p.107617-107617, Article 107617
• Main Authors: Karathanou, Konstantina, Lazaratos, Michalis, Bertalan, Éva, Siemers, Malte, Buzar, Krzysztof, Schertler, Gebhard F.X., del Val, Coral, Bondar, Ana-Nicoleta
• Format: Article
• Language: English
• Subjects: ACE2; Algorithms; Angiotensin-Converting Enzyme 2; Betacoronavirus - chemistry; Betacoronavirus - physiology; Bimolecular structure; Computational Biology - methods; Computer Graphics; Conformational plasticity; Coronavirus Infections - virology; COVID-19; Dynamic hydrogen-bond clusters; Humans; Hydrogen Bonding; Models, Molecular; Pandemics; Peptidyl-Dipeptidase A - chemistry; Peptidyl-Dipeptidase A - metabolism; Pneumonia, Viral - virology; Protein Binding; Protein Interaction Domains and Motifs; Protein Interaction Mapping - methods; Protein Interaction Maps; Protein Structure, Quaternary; Protein Structure, Secondary; SARS-CoV-2; SARS-CoV-2 protein S; Spike Glycoprotein, Coronavirus - chemistry; Spike Glycoprotein, Coronavirus - metabolism; Virus Internalization
• ISSN: 1047-8477; 1095-8657
• DOI: 10.1016/j.jsb.2020.107617

[Display omitted] •We apply graph-based approaches to identify H-bond clusters in protein complexes.•Three conformations of spike protein S have distinct H-bond clusters at key sites.•Hydrogen-bond clusters could govern structural plasticity of spike protein S.•Protein S binds to ACE2 receptor via H-bond clusters extending deep across interface. Corona virus spike protein S is a large homo-trimeric protein anchored in the membrane of the virion particle. Protein S binds to angiotensin-converting-enzyme 2, ACE2, of the host cell, followed by proteolysis of the spike protein, drastic protein conformational change with exposure of the fusion peptide of the virus, and entry of the virion into the host cell. The structural elements that govern conformational plasticity of the spike protein are largely unknown. Here, we present a methodology that relies upon graph and centrality analyses, augmented by bioinformatics, to identify and characterize large H-bond clusters in protein structures. We apply this methodology to protein S ectodomain and find that, in the closed conformation, the three protomers of protein S bring the same contribution to an extensive central network of H-bonds, and contribute symmetrically to a relatively large H-bond cluster at the receptor binding domain, and to a cluster near a protease cleavage site. Markedly different H-bonding at these three clusters in open and pre-fusion conformations suggest dynamic H-bond clusters could facilitate structural plasticity and selection of a protein S protomer for binding to the host receptor, and proteolytic cleavage. From analyses of spike protein sequences we identify patches of histidine and carboxylate groups that could be involved in transient proton binding.