The Paths to Specific vs Nonspecific Sequence Recognition

Abstract

Our understanding of both nonspecific and specific protein-DNA interaction mechanisms raise questions related to the nature of the transient encounter states, and the structural and energetic features of the protein-DNA binding process. Here we have used the nuclease domain of colicin E7 (N-ColE7) from E. coli to complex with a 12-bp DNA as the model system to draw a picture of how a protein approaches, encounters and associates with DNA. Multiscale studies using Molecular Dynamics (MD) and Brownian Dynamics (BD) simulations were performed to provide the binding process on multiple length and timescales. We characterize the encounter states and identify the spatial and orientational aspects required for the association by BD simulations. At the atomic length-scales, we investigated the binding process by MD simulations. Several intermediate binding states, which have different positions and orientations of protein around DNA in the initial structures are postulated from the MD trajectories. The results facilitate better understanding of sequence-independent protein-DNA binding landscapes and suggest pathways with favorable intermediate binding states common to both specific and nonspecific complexes.