posted on 2021-05-21, 12:35authored byCui Liu, Change Lv, Yu-ying Yao, Xue Du, Dong-xia Zhao, Zhong-zhi Yang
The recognition mechanism of oxidative damage in organisms has
long been a research hotspot. Water is an important medium in the
recognition process, but its specific role remains unknown. There
is a need to develop a suitable force field that can adequately describe
the electrostatic, hydrogen bond, and other interactions among the
molecules in the complex system of the repair enzyme and oxidized
base. The developing ABEEM polarizable force field (PFF) has been
used to simulate the repaired enzyme hOGG1 and oxidized DNA (PDB ID: 1EBM) in a biological
environment, and the corresponding results are better than those of
the fixed-charge force fields OPLS/AA and AMBER OL15. 8-Oxo-G is recognized
by Gln315 of hOGG1 mainly through hydrogen bonds mediated by continuous
exchange of 2 water molecules. Phe319 and Cys253 are stacked on both
sides of the π planes of bases to form sandwich structures.
The charge polarization effect gives an important signal to drive
the exchange of water molecules and maintains the recognition of oxidation
bases by enzymes. The mediated main water molecule A and mediated auxiliary water molecule B together
pull Gln315 to recognize 8-oxo-G by hydrogen bond interactions. Then,
the charge polarization signal of solvent water molecule C with a large absolute charge causes the absolute charge of O atoms
in water molecule A or B to increase
by approximately 0.2 e, and water molecule A or B leaves Gln315 and 8-oxo-G. The other water molecule and
water molecule C synergistically recognize 8-oxo-G
with Gln315. Even though the water molecules between Gln315 and 8-oxo-G
are removed, the MD simulation results show that water molecules appear
between Gln315 and 8-oxo-G in a very short time (<2 ps). The dwell
time of each water molecule is approximately 60 ps. The radial distribution
function and dwell time support the correctness of the above mechanism.
These polarization effects and hydrogen bonding interactions cannot
be simulated by a fixed-charge force field.