TY - JOUR
T1 - Diffusion of ring-shaped proteins along DNA
T2 - case study of sliding clamps
AU - Daitchman, Dina
AU - Greenblatt, Harry M.
AU - Levy, Yaakov
N1 - This work was supported by the Kimmelman Center for Macromolecular Assemblies and the Minerva Foundation. Y.L. holds The Morton and Gladys Pickman professional chair in Structural Biology. We are grateful for Netaly Khazanov for valuable preliminary calculations of PCNA that helped us to formulate the questions of its sliding dynamics and to Dana Krepel for suggestions and assistance.
PY - 2018/7/6
Y1 - 2018/7/6
N2 - Several DNA-binding proteins, such as topoisomerases, helicases and sliding clamps, have a toroidal (i.e. ring) shape that topologically traps DNA, with this quality being essential to their function. Many DNA-binding proteins that function, for example, as transcription factors or enzymes were shown to be able to diffuse linearly (i.e. slide) along DNA during the search for their target binding sites. The protein's sliding properties and ability to search DNA, which often also involves hopping and dissociation, are expected to be different when it encircles the DNA. In this study, we explored the linear diffusion of four ring-shaped proteins of very similar structure: three sliding clamps (PCNA, beta-clamp, and the gp45) and the 9-1-1 protein, with a particular focus on PCNA. Coarse-grained molecular dynamics simulations were performed to decipher the sliding mechanism adopted by these ring-shaped proteins and to determine how the molecular properties of the inner and outer ring govern its search speed. We designed in silico variants to dissect the contributions of ring geometry and electrostatics to the sliding speed of ring-shaped proteins along DNA. We found that the toroidal proteins diffuse when they are tilted relative to the DNA axis and able to rotate during translocation, but that coupling between rotation and translocation is quite weak. Their diffusion speed is affected by the shape of the inner ring and, to a lesser extent, by its electrostatic properties. However, breaking the symmetry of the electrostatic potential can result in deviation of the DNA from the center of the ring and cause slower linear diffusion. The findings are discussed in light of earlier computational and experimental studies on the sliding of clamps.
AB - Several DNA-binding proteins, such as topoisomerases, helicases and sliding clamps, have a toroidal (i.e. ring) shape that topologically traps DNA, with this quality being essential to their function. Many DNA-binding proteins that function, for example, as transcription factors or enzymes were shown to be able to diffuse linearly (i.e. slide) along DNA during the search for their target binding sites. The protein's sliding properties and ability to search DNA, which often also involves hopping and dissociation, are expected to be different when it encircles the DNA. In this study, we explored the linear diffusion of four ring-shaped proteins of very similar structure: three sliding clamps (PCNA, beta-clamp, and the gp45) and the 9-1-1 protein, with a particular focus on PCNA. Coarse-grained molecular dynamics simulations were performed to decipher the sliding mechanism adopted by these ring-shaped proteins and to determine how the molecular properties of the inner and outer ring govern its search speed. We designed in silico variants to dissect the contributions of ring geometry and electrostatics to the sliding speed of ring-shaped proteins along DNA. We found that the toroidal proteins diffuse when they are tilted relative to the DNA axis and able to rotate during translocation, but that coupling between rotation and translocation is quite weak. Their diffusion speed is affected by the shape of the inner ring and, to a lesser extent, by its electrostatic properties. However, breaking the symmetry of the electrostatic potential can result in deviation of the DNA from the center of the ring and cause slower linear diffusion. The findings are discussed in light of earlier computational and experimental studies on the sliding of clamps.
U2 - https://doi.org/10.1093/nar/gky436
DO - https://doi.org/10.1093/nar/gky436
M3 - مقالة
SN - 0305-1048
VL - 46
SP - 5935
EP - 5949
JO - Nucleic acids research
JF - Nucleic acids research
IS - 12
ER -