Dynamic Coupling among Protein Binding, Sliding, and DNA Bending Revealed by Molecular Dynamics

Abstract

Protein binding to DNA changes the DNA's structure, and altered DNA structure can, in turn, modulate the dynamics of protein binding. This mutual dependency is poorly understood. Here we investigated dynamic couplings among protein binding to DNA, protein sliding on DNA, and DNA bending by applying a coarse-grained simulation method to the bacterial architectural protein HU and 14 other DNA-binding proteins. First, we verified our method by showing that the simulated HU exhibits a weak preference for A/T-rich regions of DNA and a much higher affinity for gapped and nicked DNA, consistent with biochemical experiments. The high affinity was attributed to a local DNA bend, but not the specific chemical moiety of the gap/nick. The long-time dynamic analysis revealed that HU sliding is associated with the movement of the local DNA bending site. Deciphering single sliding steps, we found the coupling between HU sliding and DNA bending is akin to neither induced-fit nor population-shift; instead they moved concomitantly. This is reminiscent of a cation transfer on DNA and can be viewed as a protein version of polaron-like sliding. Interestingly, on shorter time scales, HU paused when the DNA was highly bent at the bound position and escaped from pauses once the DNA spontaneously returned to a less bent structure. The HU sliding is largely regulated by DNA bending dynamics. With 14 other proteins, we explored the generality and versatility of the dynamic coupling and found that 6 of the 15 assayed proteins exhibit the polaron-like sliding.

Direct Comparison of Amino Acid and Salt Interactions with Double-Stranded and Single-Stranded DNA from Explicit-Solvent Molecular Dynamics Simulations

“…96 The present data should allow a similar approach to be used to derive potential functions for amino acid interactions with the bases, sugar and phosphate groups of DNA in both the single- and double-stranded states. CG simulation models have already been used in a number of very interesting studies of protein-DNA interactions; see, for example, the works of the Levy 97, 98 and Takada 99 groups, with at least one involving modeling of DNA in its single-stranded state. 100 The use of potential functions derived from atomistic simulations that have been shown to reproduce relative affinities of amino acids for dsDNA and ssDNA, could enable such simulations to achieve even higher levels of realism, especially in modeling processes such as DNA replication, in which both single- and double-stranded forms of DNA play important roles.…”

Facile Assembly/Disassembly of DNA Nanostructures Anchored on Cell-Mimicking Giant Vesicles

“…As we know, membrane physico-chemical properties have a significant impact in dynamic behavior of DNA nanostructures and their assemblies. 26–29 This means that DNA nanostructures on these synthetic model membranes would be remarkably different from their dynamic behavior on the natural membrane. 30 Thus, it is necessary to study the dynamic behavior of DNA nanostructures on cell-mimicking giant vesicles model which would further advance our understanding on behavior of DNA nanostructures on biological interfaces.…”

Chromatin remodelers couple inchworm motion with twist-defect formation to slide nucleosomal DNA

“…Histone octamer, remodeler and DNA interact via excluded volume, long-range electrostatics and hydrogenbonds. For excluded volume, we employ bead-type dependent radii derived from a database of protein-protein and protein-DNA complexes (Brandani et al, 2018;Niina et al, 2017;Tan, Terakawa, & Takada, 2016).…”

“…Histone octamer, remodeler and DNA interact via excluded volume, long-range electrostatics and hydrogenbonds. For excluded volume, we employ bead-type dependent radii derived from a database of protein-protein and protein-DNA complexes 32,38,63 . Following our previous protocol 32,38 , electrostatics is modeled according to Debye-Hückel theory, with standard unit charges placed on DNA phosphate groups and protein residues in flexible regions, and fractional charges on protein residue in folded regions derived using the RESPAC method, which optimizes the coarse-grained electrostatic potential against the all-atom one in the folded conformation 64 .…”