Aug 31 2020
An extraordinary nanomachine performed a small but significant step towards an effective immune reaction. Simulations are used by scientists to figure out its operation.
Lars Schäfer and his team use simulations to clarify the structure and dynamics of proteins. Image Credit: © Ruhr University Bochum, Kramer.
The human immune system must first identify the diseased cells before it can kill them. The supposed peptide-loading complex has a crucial role to play in this process. In association with collaborators from Forschungszentrum Jülich, a team of researchers from Ruhr-Universität Bochum has examined this new nanomachine in atomic detail.
They reported the study findings in the Proceedings of the National Academy of Sciences (PNAS) on August 11th, 2020.
Cells that carry a carcinogenic mutation or are infected by a virus, for instance, synthesize proteins that are foreign to the body. The breakdown of these exogenous proteins within the cells results in antigenic peptides. These peptides are loaded by the peptide-loading complex onto the supposed major histocompatibility complex molecules (MHC) and subsequently presented on the surface of the cell.
At the cell surface, the antigenic peptides are particularly detected by T-killer cells, which eventually eliminate the infected cells. This is the method by which the immune system protects humans from pathogens.
Machine Operates with Atomic Precision
The function of the peptide-loading complex is to make sure that the MHC molecules are properly loaded with antigens.
The peptide-loading complex is a biological nanomachine that has to work with atomic precision in order to efficiently protect us against pathogens that cause disease.
Lars Schäfer, Professor and Head of Molecular Simulation Research Group, Centre for Theoretical Chemistry, Ruhr University Bochum
In earlier research works, other scientists used cryo-electron microscopy and successfully established the structure of the peptide-loading complex but with a resolution of just around 0.6 to 1.0 nm—that is, not in atomic detail.
Depending on such experimental data, Schäfer’s group in association with Professor Gunnar Schröder from Forschungszentrum Jülich has now successfully produced an atomic structure of the peptide-loading complex.
Exploring Structure and Dynamics
The experimental structure is impressive. But only with our computer-based methods were we able to extract the maximum information content contained in the experimental data.
Lars Schäfer, Professor and Head of Molecular Simulation Research Group, Centre for Theoretical Chemistry, Ruhr University Bochum
Using the atomic model, the team conducted comprehensive molecular dynamics computer simulations of the peptide-loading complex and was able to study both the structure and dynamics of the biological nanomachine.
Considering that the simulated system is very large with its 1.6 million atoms, the calculating time at the Leibniz Supercomputing Centre in Munich helped with this job significantly.
Using the high-performance computer, we were able to push into the microsecond time scale in our simulations. This revealed the role of sugar groups bound to the protein for the mechanism of peptide loading, which had previously only been incompletely understood.
Dr Olivier Fisette, Postdoc Researcher, Ruhr University Bochum
Dr Fisette is part of the Molecular Simulation Research Group.
Direct Intervention in Immune Processes
At present, the atomic model of the peptide-loading complex enables additional research works. For instance, certain viruses attempt to cheat the human immune system by selectively turning off specific elements of the peptide-loading complex.
“One feasible objective we’d like to pursue is the targeted intervention in these processes,” Schäfer concluded.
The study was financially supported by the German Research Foundation as part of the Cluster of Excellence Ruhr Explores Solvation Resolv (EXC 2033).
Journal Reference:
Fisette, O., et al. (2020) Atomistic structure and dynamics of the human MHC-I peptide-loading complex. Proceedings of the National Academy of Sciences. doi.org/10.1073/pnas.2004445117.