Mechanistic insights into the interaction of emerging SARS-CoV-2 spike variants with the transferrin receptor

Since the onset of the COVID-19 pandemic, SARS-CoV-2 has posed a substantial threat to global health and safety. While the virus's entry into human cells via the interaction of its spike protein with the angiotensin-converting enzyme 2 (ACE2) receptor is well-established, emerging studies suggest that the transferrin receptor protein (TfR) may also serve as an entry receptor. However, the precise binding mechanism between SARS-CoV-2 and TfR remains elusive, and how various SARS-CoV-2 variants interact with TfR warrants further exploration. In this study, we utilized molecular docking to model the interaction between the receptor-binding domain (RBD) of the SARS-CoV-2 spike protein and TfR, discovering that T478K and N481K mutations on the Spike RBD exhibit tight binding to TfR through salt bridges. Steered molecular dynamics (SMD) simulations were also conducted to uncover the dynamic and mechanical properties of this interaction, confirming that the overall binding affinity of LB.1 and KP.3.1.1 to TfR is enhanced. Our findings provide essential insights into the binding characteristics of both wild-type and variant SARS-CoV-2 forms, offering valuable knowledge that may inform future research on viral mutation trajectories, infection mechanisms, and therapeutic development against COVID-19.