Effect of CTerm of human albumin on the aggregation propensity of Aβ1-42 peptide: a potential of mean force study

Alzheimer’s disease (AD) is the most common progressive neurodegenerative brain disorder. It is characterized by the presence of extracellular aggregated fibrillary form of amyloid beta (Aβ) peptide and intraneuronal neurofibrillary tangles caused by the hyperphosphorylation of tau protein. Monomeric form of Aβ peptide in α-conformation is not toxic but it can undergo self-aggregation to form β-conformation which is neurotoxic. The most promising approach to combat AD is to prevent the self-aggregation of Aβ peptide. Recently, it has been reported that C-terminal (CTerm) of human albumin (HA) binds to the Aβ1–42 peptide and impairs the Aβ1–42 aggregation and promotes disassembly of Aβ1–42 aggregates. In this work, using potential of mean force (PMF) and binding free energy (BFE) calculations, we have demonstrated the effect of CTerm of HA on the dimerization of Aβ1–42 peptide. From the PMF profile, we noticed Aβ1–42-CTerm Heterodimer (10.99 kcal mol − 1) complex to have higher disassociation energy than Aβ1–42-Aβ1–42 homodimer (2.23 kcal mol − 1) complex. And also from the BFE calculations, we found that the binding affinity between Aβ1–42 peptide and CTerm (ΔGbind = −32.27 kcal mol − 1 from MM-GBSA and ΔGbind = −2.83 kcal mol − 1 from MM-PBSA (molecular mechanics–Poisson − Boltzmann surface area)) to be stronger than the Aβ1–42 peptide and another Aβ1–42 peptide (ΔGbind = −16.20 kcal mol − 1 from MM-GBSA and ΔGbind = −1.95 kcal mol − 1 from MM-PBSA). In this study, our findings from PMF and BFE analysis of the two complexes provide salient structural, binding and unbinding features and thermodynamics that support the ability of CTerm of HA in affecting the dimerization of Aβ1–42. Communicated by Ramaswamy H. Sarma