Dissecting the Molecular Basis of Host Leucine-Rich Repeat Containing 15 Mediated Interaction with Receptor Binding Domain of SARS-CoV-2 Spike Protein: A Computational Approach

The detection of leucine-rich repeat containing 15 (LRRC15) as a connecting link with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) underscores the possibility of its involvement in differential restriction activity of SARS-CoV-2 pathways. However, the structure-function mechanism of LRRC15 involving the receptor binding domain (RBD) of the SARS-CoV-2 spike protein and their mode of interaction is largely unknown. Using state-of-the-art AlphaFold2 and all-atom molecular dynamics simulations, our findings provide evidences of alternative binding modes of RBD with LRR units of LRRC15 having varied affinities. Contribution of both the receptor binding regions in RBD, including receptor binding motif in accommodating the LRR domain, towards the C-terminal region, emphasizes its differential role in modulating host cell receptiveness for SARS-CoV-2, the innate immune system, as well as antiviral tone. However, further experimental validations are necessary for unravelling the unknown mechanism and distinctive features of this host receptor in the COVID-19 pandemic, involving both the transmembrane as well as cytoplasmic domain.