Familial Alzheimer's disease (FAD) is passed down in family, which account for 2-3% of about 40 million AD cases worldwide. The Flemish (A21G) mutant of amyloid beta (A beta) exhibits unique properties among, all hereditary mutants of FAD, including the lowest aggregation rate. Recent studies showed that A beta oligomers play a key role in Alzheimer's disease (AD) pathogenesis. They could insert themselves in brain cell membrane, disrupting the membrane integrity and ion homeostasis. However, experimental studies of transmembrane oligomers have been limited due to their intrinsic heterogeneity. In this work, we extensively studied the A21G mutant of the transmembrane 3A beta(11-40) (A21G 3A beta(11-40)) using temperature replica exchange molecular dynamics (REMD) simulations. Results provide detailed information on the conformational distribution and dynamics of transmembrane A21G 3A beta(11-40). Minimal local change from A to G leads to significant conformational changes and wider free energy holes on the free energy surface as well as altered surface charges that lead to weaker affinity to the dipalmitoylphosphatidylcholine (DPPC) lipid bilayers. These results are consistent with experimental data that showed that A21G mutants of A beta peptides have lower aggregation rates and membrane binding rates.