Impact of Deamidation on the Structure and Function of Antiapoptotic Bcl-x L .

Bcl-x L is an antiapoptotic mitochondrial trans-membrane protein, which is known to play a crucial role in the survival of tumor cells. The deamidation of Bcl-x L is a pivotal switch that regulates its biological function. The potential impact of deamidation on the structure and dynamics of Bcl-x L is directly linked to the intrinsically disordered region (IDR), which is the main site for post-translational modifications (PTMs). In this study, we explored deamidation-induced conformational changes in Bcl-x L to gain insight into its loss of function by performing microsecond-long molecular dynamics (MD) simulations. MD simulation outcomes showed that the IDR motion and interaction patterns have changed notably upon deamidation. Principal component analysis (PCA) demonstrates significant differences between wild-type and deamidated Bcl-x L and suggests that deamidation affects the structure and dynamics of Bcl-x L . The combination of clustering analysis, H-bond analysis, and PCA revealed changes in conformation, interaction, and dynamics upon deamidation. Differences in contact patterns and essential dynamics that lead to a narrowing in the binding groove (BG) are clear indications of deamidation-induced allosteric effects. In line with previous studies, we show that the IDR plays a very important role in the loss of apoptotic functions of Bcl-x L while providing a unique perspective on the underlying mechanism of Bcl-x L deamidation-induced cell death.