Proline isomerization effects in the amyloidogenic protein β2-microglobulin
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Carla Molteni
The protein β2-microglobulin (β2-m) can aggregate in insoluble amyloid fibrils, which deposit in the skeletal muscle system of patients undergoing long-term haemodialysis. The molecular mechanisms of such amyloidogenesis are still not fully understood. A potential, although debated, triggering factor is the cis to trans isomerization of a specific proline (Pro32) in β2-m. Here we investigate this process in the native protein and in the aggregation-prone mutant D76N by means of molecular dynamics and the enhanced sampling method metadynamics. Our simulations, including the estimation of the free energy difference between the cis and trans isomers, are in good agreement with in vitro experiments and highlight the importance of the hydrogen bond and hydrophobic interaction network around the critical Pro32 in stabilizing and de-stabilizing the two isomers.
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Physical Chemistry Chemical Physics (PCCP) is an international journal co-owned by 19 physical chemistry and physics societies from around the world. This journal publishes original, cutting-edge research in physical chemistry, chemical physics and biophysical chemistry. To be suitable for publication in PCCP, articles must include significant innovation and/or insight into physical chemistry; this is the most important criterion that reviewers and Editors will judge against when evaluating submissions. The journal has a broad scope and welcomes contributions spanning experiment, theory, computation and data science. Topical coverage includes spectroscopy, dynamics, kinetics, statistical mechanics, thermodynamics, electrochemistry, catalysis, surface science, quantum mechanics, quantum computing and machine learning. Interdisciplinary research areas such as polymers and soft matter, materials, nanoscience, energy, surfaces/interfaces, and biophysical chemistry are welcomed if they demonstrate significant innovation and/or insight into physical chemistry. Joined experimental/theoretical studies are particularly appreciated when complementary and based on up-to-date approaches.











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