Abstract
Several dozen mutations in the large human spastin enzyme assembly have been associated with mobility impairment in hereditary spastic paraplegias. Some of them impact the structural determinants of two functional conformations of the protein, spiral and ring. Here we investigate the possible effect of the mutations on the transition between the two conformations, which is essential for the enzymatic function. By performing a variety of molecular simulations (including metadynamics) on the closely related protein katanin, we suggest that about one fourth of the known disease-associated mutations affect the transition and/or the stability of a previously unrecognized intermediate. The protocol used here can be applied to the study of conformational changes in other large biomolecular complexes.
Significance Statement By combining molecular dynamics and enhanced sampling simulations with custom-designed collective variables, we explore transient intermediate states in a large protein assembly, the severing enzyme katanin. This enzyme plays a critical role in neuronal microtubule remodeling. By targeting the transition between the spiral and ring conformations of the protein, we reveal mechanisms associated with neurodegenerative mutations that impair the function of spastin, a structurally and functionally similar enzyme. These findings provide insights that may inform future therapeutic strategies. They also expand our ability to simulate molecular processes relevant to health and disease, as our approach can be readily applied to study structural changes in other complex biological systems.
Competing Interest Statement
The authors have declared no competing interest.
Footnotes
No competing interests.
