Understanding Function and Inhibition of the Enzyme Caspase-1 Through Molecular Dynamics Simulations

Caspase-1 plays a crucial role in inflammation and immune response, making it a key target in drug development for conditions such as autoimmune diseases and neuroinflammation.

Our research has uncovered an unusual reaction mechanism for this cysteine protease, challenging the conventional view of its catalytic process. Using state-of-the-art QM/MM molecular dynamics simulations, we revealed that the catalytic histidine does not directly participate in proton transfer events�resolving a long-standing experimental puzzle. These insights not only enhance our fundamental understanding of enzyme reactivity but also provide valuable guidance for the rational design of novel inhibitors. You can see the results of this work at European Journal of Medicinal Chemistry and ACS Catalysis