Specific recognition between intrinsically disordered LEF and DNA

Lymphoid enhancer-binding factor-1 (LEF-1) is a sequence-specific and cell type-specific transcription factor in regulation of the human T cell receptor α enhancer. It has been shown the minor groove of DNA can bind the intrinsic disordered LEF. To get an insight into the mechanism of how the intrinsic disordered LEF specifically recognizes DNA, we have performed explicit-solvent multiple molecular dynamics (MD) simulations to study the specific recognition between DNA and LEF. Room-temperature MD simulations suggest that the disordered C-tails of LEF have nonspecific and specific interactions with the minor groove of DNA. Kinetic analysis of high-temperature MD simulations shows that bound and apo-states unfold via a two-state process. The specific binding of the disordered C-tails of LEF can accelerate the formation of a complex. Gly38Ala and Met11Gly mutant simulations show that electrostatic interactions between DNA and LEF significantly decrease. Kolmogorov–Smirnov (KS) P test analysis illustrates that the specific recognition between DNA and LEF might follow an induced-fit mechanism. Furthermore, these methods can be used for the research of specific recognition between DNA and other intrinsic disordered proteins.