The effect of V155M mutation on the complex of hSTING and 2′3′-cGAMP: an in silico study case

Abstract

Human stimulator of interferon genes protein (hSTING) is an essential signaling adaptor and a cytosolic DNA sensor (CDS) that functions as a homodimer in innate immunity. Natural mutation V155M in hSTING can cause hSTING-associated vasculopathy with onset in infancy (SAVI) which is an autoinflammatory disease. However, the mechanisms between the variant and SAVI are poorly understood. To explore the mechanisms, we performed all-atom molecular dynamics (MD) simulations on the complexes of wild type (WT)/mutated (V155M) hSTING and endogenous agonist 2′3′-cyclic guanosine monophosphate–adenosine monophosphate (2′3′-cGAMP) to investigate whether the interaction between hSTING and 2′3′-cGAMP could be affected by natural mutation V155M, which plays a crucial role in SAVI disease. Based on the MD simulations, the dynamic cross-correlation analysis and principal component analysis indicated that the single point mutation on residue 155 from valine to methionine changed some residues' motions of hSTING. Furthermore, MM/PBSA calculation, hydrogen bond analysis and energy decomposition analysis showed that this single point mutation increased the binding affinity of 2′3′-cGAMP with hSTING. Finally, residual network analysis indicated the way that the V155M mutation around 17 Å from the binding site controlled the strength of binding interaction and the conformation change of the substructure. These results will help in the understanding of the mechanism of SAVI disease induced by hSTING mutation at the molecular level, and provide new ideas to design innovative drugs targeted on hSTING.