The Molecular Dynamics Study on the PATHOGENICITy of Cystatin C Mutant

Abstract

Cystatin C can inhibit cysteine proteases and performs important physiological functions in cells. This protein is involved in the formation of amyloid fibers, and usually found in patients with Alzheimer's diseases or Down syndromes. Experimental evidence indicates that the mutation of human cystatin C 66th position, named L66Q is more likely to form dimers, which self-assemble subsequently to form amyloid deposits. However, the details about how the L66Q forms amyloid deposits are not clear. Here we used MD simulations and revealed that the single-site mutation in the 68th position of chicken cystatin C will cause changes in structural characteristics. The I68Q mutant has a higher fibro genic tendency than the wt, and the I68Q mutant has a tendency to “open” compared to the wt. The Loop1 region of I68Q has greater flexibility, and are easier to form dimers through domain exchange than wt, followed by further forming amyloid fiber deposits. Our study results are consistent with previous experimental conclusions, and provide a new idea for the future research of similar proteins. Besides, our conclusions also afford a solid theoretical basis for conquering amyloid diseases caused by cystatin C from a structural perspective.