Molecular Dynamics Simulation On The Effect Of Site Mutation On The Structure And Aggregation Properties Of Cystatin

Cerebral amyloid angiopathy and Alzheimer’s disease caused by cystatinamyloid mutant amyloid aggregation in the human body. To date, it lacked ofexperimental proof of mechanism that how the monomer form to dimer by theconformational transition.In this study, based on the early biochemical and cellular research, using themethod of molecular dynamics simulation，study of the effect of site mutation on thestructure and properties of cystatin. Our results showed that I66Q mutant exhibitedrelatively large secondary structure changes and obvious expanding tendency ofhydrophobic core compared to wild-type cC. The structural analysis on cystatinmonomer suggested that structural changes of the AS might make the hydrophobiccore expand more easily. In addition, analysis on docking dimer has shown that thedistorted AS was favor to intermolecular interactions between two cystatin monomers.Simulation results show that the I108T plays a role in promoting aggregation of I66Q.The appendant structure (AS) showed a larger displacement than WT and distortiontowards the hydrophobic core in I66Q/I108T.Moreover, Residue Val55plays asignificant role in the hinge loop of the cC. It was found that both V55N and V55Dcould enhance the structural stability of cC I66Q, especially in the case of V55N.Future research indicates that there were more hydrogen bonds related with position55in V55N and V55D mutants. This led to increasing the stability of Loop1andβ2-β3, which stabilized the α-helix and hydrophobic core of cC I66Q.These results might help to reveal the possible role of important residues in theprocess of cystatin domain swapping and also provide potent clues for exploring thepotential critical domains in domain swapping associated with hydrophobic core.