Computational insights into the conformational transition of STING: mechanistic, energetic considerations, and the influence of crucial mutations

Abstract

AbstractSTING (stimulator of interferon genes) is a crucial protein in the innate immune system’s response to viral and bacterial infections. In this study, we investigated the mechanistic and energetic mechanism of the conformational transition process of STING activated by cGAMP binding. We found that the STING connector region undergoes an energetically unfavorable transition during this process, which is compensated by the favorable interaction between cGAMP and the STING ligand binding domain. We utilized enhanced sampling methods to study STING’s rotation and finds that several disease-causing mutations, such as N154S and V155L, can result in a smoother transition process, while V147L exhibits unfavorable conformational transition energy. These findings indicate that V147L may not be a gain-of-function mutation, as previously thought, and are further supported by an evolutionary analysis of the STING connector region. Overall, our study provides detailed insights into the mechanism of STING’s rotation and has implications for the development of treatments for STING-related diseases.