Conformational transitions of caspase-6 in substrate-induced activation process explored by perturbation-response scanning combined with targeted molecular dynamics

• Main Authors: Shuheng Huang, Hu Mei, Laichun Lu, Zuyin Kuang, Yu Heng, Lei Xu, Xiaoqi Liang, Minyao Qiu, Xianchao Pan
• Format: Article
• Language: English
• Published: Elsevier 2021-01-01
• Series: Computational and Structural Biotechnology Journal
• Subjects: Caspase-6; Conformational transition; Perturbation-response scanning; Targeted molecular dynamics; H-bond interactions
• Online Access: http://www.sciencedirect.com/science/article/pii/S200103702100307X

Caspase-6 participates in a series of neurodegenerative pathways, and has aroused widespread attentions as a promising molecular target for the treatment of neurodegeneration. Caspase-6 is a homodimer with 6 central-stranded β-sheets and 5 α-helices in each monomer. Previous crystallographic studies suggested that the 60′s, 90′s and 130′s helices of caspase-6 undergo a distinctive conformational transition upon substrate binding. Although the caspase-6 structures in apo and active states have been determined, the conformational transition process between the two states remains poorly understood. In this work, perturbation-response scanning (PRS) combined with targeted molecular dynamics (TMD) simulations was employed to unravel the atomistic mechanism of the dynamic conformational transitions underlying the substrate-induced activation process of caspase-6. The results showed that the conformational transition of caspase-6 from apo to active states is mainly characterized by structural rearrangements of the substrate-binding site as well as the conformational changes of 60′s and 130′s extended helices. The H-bond interactions between L1, 130′s helix and 90′s helix are proved to be key determinant factors for substrate-induced conformational transition. These findings provide valuable insights into the activation mechanism of caspase-6 as well as the molecular design of caspase-6 inhibitors.