A Computational Examination of the Binding Interactions of Amyloid β and Human Cystatin C

The physiological role of human cystatin C (HCC) in the brain of individuals suffering from Alzheimer’s disease (AD) is currently an uncertainty in the scientific community. The protein complex interface between HCC and amyloidβ (Aβ), an aggregated protein in the AD brain, is of great interest due to the potential roles of HCC as an agonist and/or antagonist in AD progression. Thus, to understand the molecular details of HCC–Aβ interactions, all-atom molecular dynamic simulations were performed in explicit water under physiological conditions. Rigid body protein–protein docking was utilized to obtain the best modes of interactions between Aβ and HCC by using energy functions that comprise pairwise shape complementarity with desolvation and electrostatics. Subsequently, two top docking structures were simulated and evaluated for molecular interactions. A detailed trajectory analysis indicates favorable binding conformations between Aβ and HCC where Aβ goes through major conformational rearrangements while HCC retains its major secondary structures throughout the simulations. Root mean square deviation, radius of gyration and solvent accessible surface area analyses also suggest a larger conformational sampling for Aβ in comparison to HCC. Moreover, hydrogen bonding and hydrophobic interactions were found to have important roles in the stability of complexes between Aβ and HCC. Overall, the results obtained from this study provide molecular insight into the interaction pathways of Aβ and HCC and emphasize the importance of noncovalent forces in biomolecular interactions of therapeutic significance