Alzheimer`s disease is the most expensive condition for health care providers in the industrialized nations. The pathogenic processes are most often associated with changes in metabolism of amyloid precursor protein, most notably to the function of the membrane embedded protease gamma-secretase. In the last twenty years more than a hundred different therapeutic approaches that target amyloid metabolism and gamma-secretase have failed. Some therapies have even enhanced the cognitive decline characteristic associated with the disease. Future drug-development efforts depend on insights into gamma- secretase structure and function. Experimental: Gamma-secretase structures at 3.4 Å resolution were analyzed using multiscale molecular dynamic approaches and electrostatic calculations. Results: Gamma-secretase can guide its long amyloid peptides into its active site by its nicastrin domain. The substrate is then processively cleaved by penetration of its negatively charged C-terminal through the enzyme active site, which is dominated by the negatively charged Asp257 and Asp385. The high density of negative charges in the hydrophobic protein interior leads to highly dynamic structural changes in the residues 250-280 and residues 375-390. These highly flexible regions can stabilize different electrostatic interactions, by forcing Asp257 or Asp385 to interact with Lys380 and the N-terminus of the cleavage residue peptide. These highly flexible motions are also affected by disease-causing mutations. Similar to the disease-causing mutations classic aspartic protease inhibitors could block dynamic structural changes in the active site and lead to interruption of the processive cleavages. All cases of interrupted cleavages result in potentially toxic accumulation of hydrophobic amyloid proteins in the cell membrane. Conclusion: Molecular dynamics studies have revealed unique functional changes in gamma-secretase structure that cannot be visualized in static measurements of protein structure. Some of the conformational changes presented in the enzyme substrate complex could be targeted in the future as novel drug design strategies.