Atomistic Molecular Dynamics Simulations of Mitochondrial DNA Polymerase gamma: Novel Mechanisms of Function and Pathogenesis

作者：Euro Liliya^*; Haapanen Outi; Rog Tomasz; Vattulainen Ilpo; Suomalainen Anu; Sharma Vivek^*

来源：Biochemistry, 2017, 56(9): 1227-1238.

DOI：10.1021/acs.biochem.6b00934

DNA polymerase gamma (Pol gamma) is a key component of the mitochondrial DNA replisome and an important cause of neurological diseases. Despite the availability of its crystal structures, the molecular mechanism of DNA replication, the switch between polymerase and exonuclease activities, the site of replisomal interactions, and functional effects of patient mutations that do not affect direct catalysis have remained elusive. Here we report the first atomistic classical molecular dynamics simulations of the human Pol gamma replicative complex. Our simulation data show that DNA binding triggers remarkable changes in the enzyme structure, including (1) completion of the DNA-binding channel via a dynamic subdomain, which in the apo form blocks the catalytic site, (2) stabilization of the structure through the distal accessory beta-subunit, and (3) formation of a putative transient replisome-binding platform in the "intrinsic processivity" subdomain of the enzyme. Our data indicate that noncatalytic mutations may disrupt replisomal interactions, thereby causing Pol gamma-associated neurodegenerative disorders.

• 出版日期2017-3-7