Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), causative agent of the coronavirus disease 2019 (COVID-19) pandemic, is thought to release its RNA genome at either the cell surface or within endosomes, the balance being dependent on spike protein stability, and the complement of receptors, co-receptors and proteases. To investigate possible mediators of pH-dependence, pKa calculations have been made on a set of structures for spike protein ectodomain and fragments from SARS-CoV-2 and other coronaviruses. Dominating a heat map of the aggregated predictions, three histidine residues in S2 are consistently predicted as destabilizing in pre-fusion (all three) and post-fusion (two of the three) structures. Other predicted features include the more moderate energetics of surface salt–bridge interactions and sidechain–mainchain interactions. Two aspartic acid residues in partially buried salt-bridges (D290–R273 and R355–D398) have pKas that are calculated to be elevated and destabilizing in more open forms of the spike trimer. These aspartic acids are most stabilized in a tightly closed conformation that has been observed when linoleic acid is bound, and which also affects the interactions of D614. The D614G mutation is known to modulate the balance of closed to open trimer. It is suggested that D398 in particular contributes to a pH-dependence of the open/closed equilibrium, potentially coupled to the effects of linoleic acid binding and D614G mutation, and possibly also A570D mutation. These observations are discussed in the context of SARS-CoV-2 infection, mutagenesis studies, and other human coronaviruses.
Highlights
Viruses must deliver their genome to the host cell, and for membrane enveloped viruses this occurs either at the cell surface, and fusion with the plasma membrane, or through fusion with an intracellular membrane, subsequent to import into the cell
It is suggested that D398 in particular contributes to a pH-dependence of the open/closed equilibrium, potentially coupled to the effects of linoleic acid binding and D614G mutation, and possibly A570D mutation
The expanding dataset of SARS-CoV-2 S protein trimers and fragments has been leveraged to yield pKa predictions that focus on a small number of amino acids, when interrogated for those that show electrostatic frustration
Summary
Viruses must deliver their genome to the host cell, and for membrane enveloped viruses this occurs either at the cell surface, and fusion with the plasma membrane, or through fusion with an intracellular membrane, subsequent to import into the cell. Coronaviruses are membrane enveloped viruses that deliver their RNA genome either through fusion at the plasma or endosomal membranes [1]. Factors that determine which fusion route dominates for a particular virus include cell-surface receptor and availability (dependent on cell type), co-receptors, spike (S) protein structural stability, and which proteases carry out the S1/S2 and S2’ cleavages [2]. The primary focus for molecular response to pH is the coronavirus spike protein, with analogy to the role of influenza hemagglutinin, where pH-dependent conformational changes underpin endosome-mediated infection [7]
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