Limited to 30 people.
Date: March 28, 2025
Event Type: Training
Format: Face-to-face (Sabancı University- Altunizade Digital Campus, İstanbul)
Topic: Computational Biology
Overview: Computing the binding energy of a drug against a mutation can be challenging and prone to error. Moreover, many models (docking [1], FoldX [2], Rosetta [3], etc.) and deep learning tools (AlphaFold3 [4], DeepDTA [5], etc.) yield protein–drug complexes and energies with limited precision and explainability. Here, we employ free energy perturbation (FEP), a simulation method in which mutational perturbations are applied stepwise to an amino acid in a protein structure by annihilating the wild-type residue and creating the mutation—hence the term “alchemistry.” Because both the initial and final conformations are physical, this method enables the calculation of mutation and relative binding energies with high precision.
In this workshop, we use the enzyme dihydrofolate reductase (DHFR), a model protein for antibiotic resistance studies as an example system. We will perform FEP simulations on single mutational variants of DHFR bound to two drugs, TMP and 4'DTMP, and calculate the relative binding energies to determine the more favorable drug. This workshop will combine theory and application. In the morning, we will first learn about the fundamentals of FEP simulation and how to perform these simulations on a high-performance computer (TRUBA), after which we will run an FEP simulation on TRUBA. Each attendee will also run an FEP simulation using their temporary account. In the afternoon, we will discuss thermodynamic cycles, how to calculate relative binding energies, and how to analyze the FEP simulations. We will examine the outputs in depth through the lenses of computation, biophysics, and evolution.
[1] https://doi.org/10.1002/jcc.21256
[2] https://doi.org/10.1093/nar/gki387
[3] https://doi.org/10.1093/bioinformatics/btq007
[4] https://doi.org/10.1038/s41586-024-07487-w
[5] https://doi.org/10.1093/bioinformatics/bty593
Related DHFR references:
- https://doi.org/10.1093/molbev/msz086
- https://doi.org/10.1021/acs.jcim.3c00818
- https://doi.org/10.1002/cpe.8371
Agenda: The training will consist of two sections: morning and afternoon sessions. Registration will start at 9:00 AM, and the first session will begin at 9:30 AM.
Level: Intermediate
Language: English
Duration: 7 Hours
Target Audience: Academia
Prerequisite(s): Participants are expected to have a knowledge of protein structure and minimal experience with molecular dynamics simulations.
About the instructor:
Tandac Furkan Guclu earned his BSc in Biology from Hacettepe University, pursued an MSc in Bioengineering at Marmara University, and completed his PhD in Molecular Biology, Genetics and Bioengineering at Sabancı University. His doctoral research delved into molecular simulations to understand protein dynamics, structure, and function. Currently, as a postdoctoral researcher at Sabancı University, he employs advanced computational techniques—including free energy perturbation simulations, high-throughput mutational scanning, and graph theory-based dynamic residue network analyses—to investigate both the structural and functional aspects of proteins.
Moderator: Dr. Canan Atılgan
Application Due: March 27, 2025
Contact: ncc@ulakbim.gov.tr
This course is offered free of charge
Notes:
Registration based on the principle of "first come – first served"
Please cancel your registration if you won't be able to attend so that others may attend.
Participants will use their own laptop or computer for the hands-on session.
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Disclaimer
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Acknowledgments
This event is supported by the EuroCC 2 and EuroCC4SEE projects, which received funding from the European High-Performance Computing Joint Undertaking (JU) under grant agreements No. 101101903 and No. 101191697, respectively. The JU receives support from the Digital Europe Programme and Germany, Bulgaria, Austria, Croatia, Cyprus, Czech Republic, Denmark, Estonia, Finland, Greece, Hungary, Ireland, Italy, Lithuania, Latvia, Poland, Portugal, Romania, Slovenia, Spain, Sweden, France, Netherlands, Belgium, Luxembourg, Slovakia, Norway, Türkiye, Republic of North Macedonia, Iceland, Montenegro, Serbia.
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