A computational examination of the binding interactions of amyloidβ and human cystatin C

Abstract

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 amyloid[Formula: see text] (A[Formula: see text]), 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–A[Formula: see text] 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 A[Formula: see text] 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 A[Formula: see text] and HCC where A[Formula: see text] 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 A[Formula: see text] in comparison to HCC. Moreover, hydrogen bonding and hydrophobic interactions were found to have important roles in the stability of complexes between A[Formula: see text] and HCC. Overall, the results obtained from this study provide molecular insight into the interaction pathways of A[Formula: see text] and HCC and emphasize the importance of noncovalent forces in biomolecular interactions of therapeutic significance.