Intrinsically Disordered Proteins by Homology Modeling and Replica Exchange Molecular Dynamics Simulations: A Case Study of Amyloid-β42

Abstract

Homology modeling emerges as a potent tool unveiling the structural enigma of intrinsically disordered proteins (IDPs), with recent advancements such as AlphaFold2 enhancing the precision of these analyses. The process usually involves identifying homologous proteins with known structures and utilizing their templates to predict the three-dimensional architecture of the target IDP. However, IDPs lack a well-defined three-dimensional structure, and their flexibility makes it difficult to accurately predict their conformations. On the other hand, special sampling molecular dynamics simulations have been shown to be useful in defining the distinct structural properties of IDPs. Here, the structural properties of the disordered amyloid-β42 peptide were predicted using various homology modeling tools including C-I-TASSER, I-TASSER, Phyre2, SwissModel and AlphaFold2. In parallel, extensive replica exchange molecular dynamics simulations of Aβ42 were conducted. Results from homology modeling were compared to our replica exchange molecular dynamics simulations and experiments for gaining insights into the accuracy of homology modeling tools for IDPs used in this work. Based on our findings, none of the homology modeling tools used in this work can capture fully the structural properties of Aβ42. However, C-I-TASSER yields a radius of gyration and tertiary structure properties that are more in accord with the simulations and experimental data rather than I-TASSER, Phyre2, SwissModel and AlphaFold2.