Exploring ligand binding pathways on proteins using hypersound–accelerated molecular dynamics

Abstract

Capturing the dynamic processes of biomolecular systems in atomistic detail remains difficult despite recent experimental advances. Although molecular dynamics (MD) techniques enable atomic-level observations, simulations of "slow" biomolecular processes (with timescales longer than submilliseconds) are challenging, due to current computer speed limitations. Therefore, we developed a new method to accelerate MD simulations by high-frequency ultrasound perturbation. The binding events between the protein CDK2 and its small-molecule inhibitors were nearly undetectable in 100-ns conventional MD, but the new method successfully accelerated their slow binding rates by up to 10-20 times. The accelerated MD simulations revealed a variety of microscopic kinetic features of the inhibitors on the protein surface, such as the existence of different binding pathways to the active site. Moreover, the simulations allowed estimating the corresponding kinetic parameters and exploring other druggable pockets. This method can thus provide deeper insight into the microscopic interactions controlling biomolecular processes. (149 /150 words)

Pepsin-like aspartic proteases (PAPs) as model systems for combining biomolecular simulation with biophysical experiments

“…23 and 24). Other enhanced sampling methods such as accelerated MD (aMD), [80][81][82] weighted ensemble (WE) method, [83][84][85] adiabatic-biased MD (ABMD) 86,87 etc can also be tested on PAPs to explore conformational dynamics, kinetics and free energy associated with ligand binding/unbinding.…”