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

4. November 2021

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

Illustration of the application of the τRAMD and MD-IFP workflow to simulate the dissociation of a drug-like compound from a target protein. The compound can dissociate via one of three paths along which different transient states are sampled and these influence the rate of dissociation from the protein.

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

About HITS

The Heidelberg Institute for Theoretical Studies (HITS) was established in 2010 by the physicist and SAP co-founder Klaus Tschira (1940-2015) and the Klaus Tschira Foundation as a private, non-profit research institute. HITS conducts basic research in the natural sciences, mathematics and computer science, with a focus on the processing, structuring, and analyzing of large amounts of complex data and the development of computational methods and software. The research fields range from molecular biology to astrophysics. The shareholders of HITS are the HITS-Stiftung, which is a subsidiary of the Klaus Tschira Foundation, Heidelberg University and the Karlsruhe Institute of Technology (KIT). HITS also cooperates with other universities and research institutes and with industrial partners. The base funding of HITS is provided by the HITS Stiftung with funds received from the Klaus Tschira Foundation. The primary external funding agencies are the Federal Ministry of Education and Research (BMBF), the German Research Foundation (DFG), and the European Union.

Switch to the German homepage or stay on this page