posted on 2022-01-31, 21:44authored byJinan Wang, Yinglong Miao
Protein–protein interactions
(PPIs) play key roles in many
fundamental biological processes such as cellular signaling and immune
responses. However, it has proven challenging to simulate repetitive
protein association and dissociation in order to calculate binding
free energies and kinetics of PPIs due to long biological timescales
and complex protein dynamics. To address this challenge, we have developed
a new computational approach to all-atom simulations of PPIs based
on a robust Gaussian accelerated molecular dynamics (GaMD) technique.
The method, termed “PPI-GaMD”, selectively boosts interaction
potential energy between protein partners to facilitate their slow
dissociation. Meanwhile, another boost potential is applied to the
remaining potential energy of the entire system to effectively model
the protein’s flexibility and rebinding. PPI-GaMD has been
demonstrated on a model system of the ribonuclease barnase interactions
with its inhibitor barstar. Six independent 2 μs PPI-GaMD simulations
have captured repetitive barstar dissociation and rebinding events,
which enable calculations of the protein binding thermodynamics and
kinetics simultaneously. The calculated binding free energies and
kinetic rate constants agree well with the experimental data. Furthermore,
PPI-GaMD simulations have provided mechanistic insights into barstar
binding to barnase, which involves long-range electrostatic interactions
and multiple binding pathways, being consistent with previous experimental
and computational findings of this model system. In summary, PPI-GaMD
provides a highly efficient and easy-to-use approach for binding free
energy and kinetics calculations of PPIs.