The development of Alzheimer's disease (AD), the most prevalent form of dementia, is associated with the abnormal aggregation of Amyloid-β (Aβ) peptides into fibrils and plaques, leading to a decline in brain function. A promising approach to treating Aβ pathology involves inhibiting fibrillogenesis and developing compounds that effectively disrupt the stable structure of Aβ fibrils. To investigate the destabilizing effects of peptides on Aβ42 protofibrils, we designed 42 different N-methylated peptides that bind to Aβ42 protofibrils. We then studied the protofibril-peptide interactions using molecular docking, free energy calculations, and molecular dynamics (MD) simulations. Our results demonstrate that peptides induce changes in the secondary structure of Aβ42 protofibrils, ultimately leading to the formation of a less ordered structure. Increased Root Mean Square Deviation (RMSD), reduced residue contacts, disrupted salt bridge interactions, and decreased hydrogen bonds between chains in the Aβ42 protofibril indicate destabilization of the protofibril structure. Among the peptides tested, P3 and P11, both singly N-methylated, exhibited the most potential for disrupting the Aβ42 protofibril structure.