The effects of energy on protein misfolding and aggregation
The effects of energy on protein misfolding and aggregation lead image
While protein misfolding and aggregation are responsible for over 600 neurologic disorders, the molecular pathology of these phenomena is poorly understood. Haque et al. present insights into the aggregation process through the analyses of amino acid sidechains in proteins.
“Protein aggregation has a significant impact on various scientific fields, ranging from biomedical research and drug development to biochemistry, material science, computational biology, and molecular biology,” said author Md. Mozzammel Haque.
Previous work by the authors determined the temperature at which misfolding occurred. By studying the interaction between the protein sidechain and the hydrophobic ligand, they found that if an external effect on the protein sidechain is higher than the stiffness of the alpha or beta hydrogen bonds of the protein backbone, the resulting proteins will be misfolded.
The authors’ current work shows that if the binding/interaction energy between protein-ligand is higher than the stiffness of the protein backbone alpha-helix hydrogen bond, the alpha-helix will be converted into a beta-sheet through unfolding. Then, if this energy is higher than the beta-sheet hydrogen bond, the protein will aggregate.
They also found that when the physiological temperature is close to the protein’s melting point, 311K, aggregation is more likely. At this temperature, proteins are in a high-energy state and are more inclined to undergo structural changes.
“This provides a physical process of aggregation at a molecular level and suggests that the ligand-binding contacts control the observed amyloid fibril architectures,” said Haque.
Understanding the structure and mechanical aspects of amyloid fibrils may provide a solution to many neurodegenerative disease therapies.
Source: “Thermodynamics of mechanopeptide sidechains,” by Md. Mozzammel Haque, Muhammad Abdul Kadir, and Richard Bayford, AIP Advances (2023). The article can be accessed at https://doi.org/10.1063/5.0154129 .
