New tools for computing protein-ligand dissociation rates and exploring dissociation mechanisms

3. November 2020

The length of time that a drug molecule spends bound to its protein target – its residence time – is an important determinant of its efficacy, and is inversely related to the rate of dissociation of the drug-target complex.  Consequently, there is a need for computational methods to predict dissociation rates to guide drug design and discovery. For most pharmaceutically relevant compounds, the timescales for dissociation from the target far exceed those that are accessible to conventional molecular dynamics simulation methods.

To address this problem, we developed and evaluated an efficient computational workflow that enables the prediction of relative drug-protein residence times and the analysis of dissociation mechanisms in an automated manner.  The workflow is based on simulations performed with the Random Acceleration Molecular Dynamics (RAMD) method which, in addition to existent implementations in the NAMD and AMBER software packages, we have now implemented in the freely available GROMACS molecular simulation engine for simulations on CPU or GPU nodes

Relative dissociation rates are computed with the tauRAMD protocol and dissociation trajectories are analyzed using protein–ligand interaction fingerprints with our new MD-IFP set of tools.  The workflow is described in Kokh et al. J. Chem. Phys. 153, 125102 (2020); doi: 10.1063/5.0019088 , recently published in a JCP Special Topic on Classical Molecular Dynamics (MD) Simulations: Codes, Algorithms, Force fields, and Applications.

Illustration of the application of the tauRAMD and MD-IFP workflow to simulating the dissociation of a drug-like compound from an anticancer target protein. The purple contours indicate the regions explored by the compound during its dissociation from the protein. The compound can dissociate via one of two main paths along which different transient states are sampled and these influence the rate of dissociation from the protein. The RAMD simulations can be carried out efficiently using the GROMACS implementation.


Kokh DB, Doser B, Richter S, Ormersbach F, Cheng X, Wade RC “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, 125102 (2020); doi: 10.1063/5.0019088, recently published in a JCP Special Topic on Classical Molecular Dynamics (MD) Simulations: Codes, Algorithms, Force fields, and Applications.

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.

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