4 research outputs found
Parameterization of Highly Charged Metal Ions Using the 12-6‑4 LJ-Type Nonbonded Model in Explicit Water
Highly charged metal ions act as
catalytic centers and structural
elements in a broad range of chemical complexes. The nonbonded model
for metal ions is extensively used in molecular simulations due to
its simple form, computational speed, and transferability. We have
proposed and parametrized a 12-6-4 LJ (Lennard-Jones)-type nonbonded
model for divalent metal ions in previous work, which showed a marked
improvement over the 12-6 LJ nonbonded model. In the present study,
by treating the experimental hydration free energies and ion–oxygen
distances of the first solvation shell as targets for our parametrization,
we evaluated 12-6 LJ parameters for 18 MÂ(III) and 6 MÂ(IV) metal ions
for three widely used water models (TIP3P, SPC/E, and TIP4P<sub>EW</sub>). As expected, the interaction energy underestimation of the 12-6
LJ nonbonded model increases dramatically for the highly charged metal
ions. We then parametrized the 12-6-4 LJ-type nonbonded model for
these metal ions with the three water models. The final parameters
reproduced the target values with good accuracy, which is consistent
with our previous experience using this potential. Finally, tests
were performed on a protein system, and the obtained results validate
the transferability of these nonbonded model parameters
Parameterization of Highly Charged Metal Ions Using the 12-6‑4 LJ-Type Nonbonded Model in Explicit Water
Highly charged metal ions act as
catalytic centers and structural
elements in a broad range of chemical complexes. The nonbonded model
for metal ions is extensively used in molecular simulations due to
its simple form, computational speed, and transferability. We have
proposed and parametrized a 12-6-4 LJ (Lennard-Jones)-type nonbonded
model for divalent metal ions in previous work, which showed a marked
improvement over the 12-6 LJ nonbonded model. In the present study,
by treating the experimental hydration free energies and ion–oxygen
distances of the first solvation shell as targets for our parametrization,
we evaluated 12-6 LJ parameters for 18 MÂ(III) and 6 MÂ(IV) metal ions
for three widely used water models (TIP3P, SPC/E, and TIP4P<sub>EW</sub>). As expected, the interaction energy underestimation of the 12-6
LJ nonbonded model increases dramatically for the highly charged metal
ions. We then parametrized the 12-6-4 LJ-type nonbonded model for
these metal ions with the three water models. The final parameters
reproduced the target values with good accuracy, which is consistent
with our previous experience using this potential. Finally, tests
were performed on a protein system, and the obtained results validate
the transferability of these nonbonded model parameters
The Role of the Active Site Flap in Streptavidin/Biotin Complex Formation
Obtaining a detailed description
of how active site flap motion affects substrate or ligand binding
will advance structure-based drug design (SBDD) efforts on systems
including the kinases, HSP90, HIV protease, ureases, etc. Through
this understanding, we will be able to design better inhibitors and
better proteins that have desired functions. Herein we address this
issue by generating the relevant configurational states of a protein
flap on the molecular energy landscape using an approach we call MT<sub>Flex‑b</sub> and then following this with a procedure to estimate
the free energy associated with the motion of the flap region. To
illustrate our overall workflow, we explored the free energy changes
in the streptavidin/biotin system upon introducing conformational
flexibility in loop<sub>3–4</sub> in the biotin unbound (<i>apo</i>) and bound (<i>holo</i>) state. The free energy
surfaces were created using the Movable Type free energy method, and
for further validation, we compared them to potential of mean force
(PMF) generated free energy surfaces using MD simulations employing
the FF99SBILDN and FF14SB force fields. We also estimated the free
energy thermodynamic cycle using an ensemble of closed-like and open-like
end states for the ligand unbound and bound states and estimated the
binding free energy to be approximately −16.2 kcal/mol (experimental −18.3
kcal/mol). The good agreement between MT<sub>Flex‑b</sub> in combination
with the MT method with experiment and MD simulations supports the
effectiveness of our strategy in obtaining unique insights into the
motions in proteins that can then be used in a range of biological
and biomedical applications
Mechanism of Formation of the Nonstandard Product in the Prenyltransferase Reaction of the G115T Mutant of FtmPT1: A Case of Reaction Dynamics Calling the Shots?
FtmPT1
is a fungal indole prenyltransferase that affords Tryprostatin
B from Brevianamide F and dimethylallyl pyrophosphate; however, when
a single residue in the active site is mutated (Gly115Thr), a novel
five-membered ring compound is obtained as the major product with
Tryprostatin B as the minor product. Herein, we describe detailed
studies of the catalysis of the Gly115Thr mutant of FtmPT1 with a
focus on the observed regioselectivity of the reaction. We employ
one- and two-dimensional potential of mean force simulations to explore
the catalytic mechanism, along with molecular dynamics simulations
exploring the reaction dynamics of the prenyl transfer reaction. Single-point
electronic structure calculations were also used to explore the performance
of the self-consistent charge density functional tight-binding method
to model specific reaction steps. Importantly, we observe that the
two reaction pathways have comparable activation parameters and propose
that the origin of the novel product is predicated, at least in part,
on the topology of the potential energy surface as revealed by reaction
dynamics studies