Abstract
Recent experiments suggest that cellular crowding facilitates the target search dynamics of proteins on DNA, the mechanism of which is not yet known. By using large scale computer simulations, we show that two competing factors, namely the width of the depletion layer that separates the crowder cloud from the DNA molecule and the degree of protein-crowder crosstalk, act in harmony to affect the target search dynamics of proteins. The impacts vary from nonspecific to specific target search regime. During a nonspecific search, dynamics of a protein is only minimally affected, whereas, a significantly different behaviour is observed when the protein starts forming a specific protein-DNA complex. We also find that the severity of impacts largely depends upon physiological crowder concentration and deviation from it leads to attenuation in the binding kinetics. Based on extensive kinetic study and binding energy landscape analysis, we further present a comprehensive molecular description of the search process that allows us to interpret the experimental findings.
Highlights
Crucial cellular processes such as transcription, DNA replication, DNA damage repair, etc. rely on recognition of the target sites located on DNA followed by formation of specific complexes by a class of proteins, often referred as DNA binding proteins (DBPs)
The interacting proteins and DNA are embedded on the mesh, the size of which varies with radius of gyration (Rg) of the polymeric crowder molecules
The dynamics of crowder and DNA molecule results into formation of a depletion layer, the existence of which is supported by the observed depletion volume around a DNA molecule under in vivo condition commonly referred as hydration shells, formed by hydration forces
Summary
Crucial cellular processes such as transcription, DNA replication, DNA damage repair, etc. rely on recognition of the target sites located on DNA followed by formation of specific complexes by a class of proteins, often referred as DNA binding proteins (DBPs). The 1D diffusion is further classified into two types: the sliding motion through the DNA major grooves and the small jumps performed by the protein on DNA surface (hopping) Each of these modes of translocation is confirmed experimentally with the recent advances in spectroscopic techniques[11,12,13,14] and single molecule experiments[15,16]. A protein searching for its target site experiences two distinctly different viscous media when performing 3D diffusion in bulk and 1D diffusion along the DNA contour respectively How such duality in the cellular environment affects the target search dynamics? Our result underscores that the fastest kinetics is achieved only at physiological crowder concentration, a deviation from which results in attenuation of the binding kinetics
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