Abstract
Amyloid fibrillar aggregates play a critical role in many neurodegenerative disorders. Conversion of globular proteins into fibrils is associated with global conformational rearrangement and involves the transformation of α-helices to β-sheets. In the present work, the accelerated molecular dynamics technique was applied to study the unfolding of hen egg-white lysozyme at elevated temperatures, and the transformation of the native structure to a disordered one was analyzed. The influence of the disulfide bonds on the conformational dynamics and the energy landscape of denaturation process was considered. Our results show that formation of the metastable β-enriched conformers of individual protein molecules may precede the aggregation process. These β-rich intermediates can play a role of bricks making up fibrils.
Communicated by Ramaswamy H. Sarma
Acknowledgments
The reported study was funded by RFBR, project number 19-315-51012 (EE, OM, and IS). EE, OM and YuZ are thankful for partial financial support from the government assignment for FRC Kazan Scientific Center of RAS. The computer simulations were carried out using the Joint Supercomputer Center of the Russian Academy of Sciences, Sirius computational cluster and the Supercomputer cluster of Sevastopol State University.
Disclosure statement
No potential conflict of interest was reported by the authors.