τRAMD – compute protein-ligand dissociation rates and explore dissociation mechanisms

Researchers from the Molecular and Cellular Modeling (MCM) group at HITS have developed and validated τRAMD (τ-Random Acceleration Molecular Dynamics),an efficient computational workflow that enables the prediction of drug-protein relative residence times and the analysis of dissociation mechanisms in an automated manner. As such, τRAMD is a flexible tool that can be implemented in rational drug design workflows for the design of new molecules or ligand optimization. 

The τRAMD protocol applies RAMD to accelerate the egress of a small molecule from a target receptor through the application of an adaptive randomly oriented force on the ligand. The workflow facilitates the identification of dissociation mechanisms and characterization of transition states through the MD-IFP (Molecular Dynamics – Interaction Fingerprint) post-analysis tool.

In addition to implementations in the NAMD and AMBER software packages, RAMD has recently been implemented in the freely available GROMACS molecular simulation engine for simulations on CPU or GPU nodes. 

References:

Kokh DB, Doser B, Richter S, Ormersbach F, Cheng X, Wade RC (2020). A workflow for exploring ligand dissociation from a macromolecule: Efficient random acceleration molecular dynamics simulation and interaction fingerprint analysis of ligand trajectories, J. Chem. Phys. 153(12):125102

Kokh DB, Amaral M, Bomke J, Grädler U, Musil D, Buchstaller H, Dreyer MK, Frech M, Lowinski M, VKokh DB, Amaral M, Bomke J, Grädler U, Musil D, Buchstaller H, Dreyer MK, Frech M, Lowinski M, Vallee F, Bianciotto M, Rak A, Wade RC (2018). Estimation of Drug-Target Residence Times by τ-Random Acceleration Molecular Dynamics Simulations, J. Chem. Theory Comput. 14(7):3859-3869