CONICET | Buscador de Institutos y Recursos Humanos

In a previous work we showed that global electrokinetic andhydrodynamic properties of amyloid-beta peptides (A?À) were needed to understandkey biophysical mechanisms associated with the amyloidogenic process found inAlzheimer?Ls Disease. In fact the A?À(12-28) peptide fragment (designated monomerhere) with an amino acid sequence expressed VHHQKLVFFAEDVGSNK,and itsdimer were characterized at low pH through the modeling of their diffusivitiesand effective electrophoretic mobilities. For this purpose diffusivityexperimental values of monomer and dimer analogues of this peptide fragment andmonomer and dimer mixtures at thermodynamic equilibrium were used as reportedin the literature for different monomer initial concentrations. Our theoreticaland numerical analyses demonstrated that peptide concentration, aggregatesizes, chain-solvent friction coefficients and near molecule pH values due tothe pair particle charge regulation phenomenon (PPCR) were crucial parametersin the amyloidogenic process. Further the PPCR phenomenon was relevant inpolypeptide interactions, and it was required to be added to the classicalintraparticle charge regulation (IPCR) phenomenon. In this framework, here we carryout an analysis of the problem described above, to show that the electrostaticfree energy change in the peptide dimerization step has an importantthermodynamic effect on the viability of the subsequent amyloidogenic process.Thus through a thermodynamic theoretical analysis we show here that the totalfree energy change can be decomposed into the conformational free energy changeplus the electrostatic free energy change giving a subtle interplay betweenthem. Thus, at a given concentration of peptide fraction, the dimerization isenhanced demonstrating the viability of the so called ?gcascade effect?h, whichforms higher order oligomers leading to insoluble aggregates and fibrils.