HPC application for candidate drug optimization using free energy perturbation calculations

Project reference: 1911

The advent of technological advances in the field of computer-aided drug design has streamlined the drug design process, making it more cost- and time-efficient. One of the most important tasks in the lead optimization phase of the drug design process is to predict, among a series of lead candidates, which ones will bind more strongly to the therapeutic target. In this direction, relative binding free energy methodologies have been developed, which rely on physics-based molecular simulations and rigorous statistical mechanics to calculate the differences in the free energy of binding between a parent candidate drug and analogues. For example, Free Energy Perturbation (FEP) calculations coupled with Molecular Dynamics (MD) simulations calculate the free energy difference between an initial (reference) and an analog (target) molecule to an average of a function of their energy difference evaluated by sampling for the initial state. In this project, free energy perturbation calculations will be performed with NAMD or GROMACS in order to test the methodology for accurate calculation of relative binding free energies between ligands in a test of >200 ligands, which requires HPC resources.

The application of free energy perturbation calculations is a promising strategy for candidate drug optimisation, as it can accurately predict among a series of lead candidates, which ones will bind more strongly to the therapeutic target

Project Mentor:  Dr. Zoe Cournia

Project Co-mentor: Dr. Dimitris Dellis

Site Co-ordinator: Sotiropoulos Aristeidis

Learning Outcomes:
Learn how to set up and perform free energy perturbation calculations coupled with Molecular Dynamics simulations. Develop own tools and scripts to automate the process. Understand the ligand-protein binding.

Student Prerequisites (compulsory):
Natural science student (Chemistry, Physics, Engineer) that have familiarity with or want to learn how to perform computer simulations.

Student Prerequisites (desirable):
Basic programming and Linux OS skills would be desirable.

Training Materials:
See www.drugdesign.gr


  • Week 1. Perform GROMACS or NAMD Tutorial. Familiarize
    with Linux OS.
  • Week 2. Setup the protein system. Read the literature on free energy perturbation calculations.
  • Week 3. Submit the Work Plan. Familiarize with HPC resources on ARIS, creating and running batch scripts. Submit the MD jobs.
  • Week 4. Familiarize with analyses tools and perform test calculations on the trajectories.
  • Week 5. Produce free energy perturbation calculations (FEP).
  • Week 6. Analyze the trajectories
  • Week 7. Rationalize the results and gain insights into lead optimization.
  • Week 8. Write the final report.

Final Product Description:
The accuracy of free energy perturbation calculations in a test set from the literature. Assessment of usage in an HPC environment for high-throughput applications.

Adapting the Project: Increasing the Difficulty:
The project can be made more difficult if we decide to code to automate the process of FEP.

Adapting the Project: Decreasing the Difficulty:
The project can be made less difficult by choosing easier analyses.

The student will need to have access to ARIS supercomputer facility, the necessary software and analysis tools to run and analyse the trajectories. Local resources for analyses will be provided (office space and desktop).

Greek Research and Technology Network S.A.

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