Probing the Binding Affinity
by Jarzynski’s
Nonequilibrium Binding Free Energy and Rupture Time
Version 2 2018-04-20, 16:20
Version 1 2018-04-20, 16:18
Posted on 2018-04-20 - 16:20
Binding affinity
of a small ligand to a receptor is the important
quantity in drug design, and it might be characterized by different
quantities. The most popular one is the binding free energy, which
can be estimated by several methods in conventional molecular dynamics
simulation. So far in steered molecular dynamics (SMD), one can use
either the rupture force or nonequilibrium pulling work as a measure
for binding affinity. In this paper, we have shown that the nonequilibrium
binding free energy ΔGneqJar, obtained by Jarzynski’s
equality at a finite pulling speed, has good correlation with experimental
data on inhibition constants, implying that this quantity can be used
as a good scoring function for binding affinity. A similar correlation
has also been disclosed for binding and unbinding free energy barriers.
Applying the SMD method to unbinding of 23 small compounds from the
binding site of β-lactamase protein, a bacteria-produced enzyme,
we have demonstrated that the rupture or unbinding time strongly correlates
with experimental data with correlation level R ≈
0.84. As follows from the Jarzynski’s equality, the rupture
time depends on the unbinding barrier exponentially. We show that
ΔGneqJar, the rupture time, and binding and unbinding
free energy barriers are good descriptors for binding affinity. Our
observation may be useful for fast screening of potential leads as
the SMD simulation is not time-consuming. On the basis of nonequilibrium
simulation, we disclosed that, in agreement with the experiment, the
binding time is much longer than the unbinding one.
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Truong, Duc Toan; Li, Mai Suan (2018). Probing the Binding Affinity
by Jarzynski’s
Nonequilibrium Binding Free Energy and Rupture Time. ACS Publications. Collection. https://doi.org/10.1021/acs.jpcb.8b02137
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