Advanced Molecular Simulations On JUWELS Booster Pave The Way For Future HIV-1 Treatments

Cyclophilin A binds to the CYPA binding loop of HIV-1 M capsid, where it can exert cis/trans isomerase activity at the G89-P90 ω dihedral. (A) Overview of the simulated complex. CYPA (shown in gray) binds to the CYPA binding loop (orange) on the surface of the HIV-1 capsid. (B) Close-up view of the CYPA binding loop. The ω dihedral between residues G89 and P90 is marked. (C) Potential of mean force (free energy profile) along the ω dihedral of G89-P90 in HIV-1 M wild type with or without CYPA.

In the fight against the enigmatic HIV-1 virus, a recent study reveals a turning point: the discovery of the virus’s Achilles’ heel, which could open new doors in HIV therapy. Learn how a team of leading scientists from Helmholtz Information has uncovered a critical vulnerability in the virus’s behavior – a breakthrough that could revolutionize the world of medicine. (Source: Jülich Supercomputing Centre – News flashes)

The global HIV-1 pandemic, with over 40 million infections, illustrates the virus’s remarkable adaptation to humans. It originated from simian immunodeficiency viruses (SIV) in chimpanzees and gorillas, with HIV-1 M being the pandemic strain. There are other non-pandemic strains, HIV-1 N, O, and P, found in a few West African individuals.

Recent research by Prof. Dr. Holger Gohlke (IBG-4, Forschungszentrum Jülich and Heinrich Heine University Düsseldorf) and Prof. Dr. Carsten Münk (University Hospital Düsseldorf) uncovered a new understanding of how HIV-1 M adapts to human cells. Human cells defend against retroviruses, like SIV, using the TRIM5α protein. However, HIV-1 M avoids this defense by binding to another protein, cyclophilin A, a trans-cis-isomerase, which suppresses TRIM5α binding.

For this, computationally intense umbrella sampling molecular dynamics simulations of HIV-capsid protein/cyclophilin A complexes were performed on the JUWELS Booster module, exploiting the excellent performance of the AMBER molecular simulation code on GPUs. Followed by configurational free energy computations, these computations indicated that capsid residue 88 can affect trans-to-cis isomerization patterns on the capsids of the tested viruses. These differential CYPA usages by pandemic and non-pandemic HIV-1 suggest that the enzymatic activity of CYPA on the viral core might be important for its protective function against human TRIM5α.

The study identifies a potential vulnerability in HIV-1, offering hope for new drugs. By suppressing the binding of cyclophilin A to the virus, researchers may develop drugs to combat HIV-1. Published in “The Proceedings of the National Academy of Sciences (PNAS),” this study paves the way for future advancements in HIV-1 treatment.

11.01.2024, Jülich Supercomputing Centre – News flashes

The original press release can be found at: 

Data-efficient Machine Learning of Biomolecules

The original publication can be found at:

Augustin P. Twizerimana, Daniel Becker, Shenglin Zhu, Tom Luedde, Holger Gohlke, and Carsten Münk, The cyclophilin A-binding loop of the capsid regulates the human TRIM5α sensitivity of nonpandemic HIV-1. Proceedings of the National Academy of Sciences (PNAS). 2023, 20, 48. DOI: 10.1073/pnas.2306374120

Localization in Helmholtz Information:

Helmholtz Research Field Information, Program 1: Engineering Digital Futures, Topic 1: Enabling Computational- & Data-Intensive Science and Engineering

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Contact:

Prof. Dr. Holger Gohlke
Institute of Bio- and Geosciences (IBG)
Bioinformatics (IBG-4)
Forschungszentrum Jülich
Phone: +49 2461/61-85550
E-Mail: h.gohlke@fz-juelich.de