An in-depth analysis of the molecular dynamics and structural aspects of IKB proteins

The transcriptional activity of nuclear factor (NF)-κB is primarily regulated by interaction with inhibitory IκB proteins. The primary role of IκB protein is masking the nuclear localization signal of NF-κB, preventing its translocation to the nucleus. Previous studies have shown that distinct IκB family members possess similar fold, however, it is still unclear how the functional differences among IκB proteins arise. In our previous study, we have reported the structure-function relationship of cytoplasmic and nuclear IκB proteins using computational approaches. However, in the study reported here, we explore the dynamic behavior of IκB proteins. We were particularly interested to investigate whether the subtle differences observed among IκB family members were associated with detectable dynamic differences. Therefore, we carried out extensive molecular dynamics simulations of IκB proteins. We observed two apparent dynamics sub-states in the nanosecond protein simulations, the transition occurring around 45 ns. Overall, this dynamic behavior is found to be consistent among all IκB members. However, MD conformers observed among IκB family members are not identical. The existence of these two apparent sub-states results from a high flexibility at the finger loop regions and a relative flexibility at the loops connecting the ankyrin repeat domains. These results suggest that although IκB proteins possess similar structures, however, the major variations observed in surface charge distribution, hydrophobicity and the conformational specificity in the finger loop regions are accountable for binding with different NF-κB subunits thereby leading to diverse functional specificity.