gamma-secretase is a membrane-embedded protease that cleaves single transmembrane helical domains of various integral membrane proteins. The amyloid precursor protein (APP) is an important substrate due to its pathological relevance to Alzheimer's disease. The mechanism of the cleavage of APP by gamma-secretase that leads to accumulation of Alzheimer's disease causing amyloid-beta (An) is still unknown. Coarse-grained molecular dynamics simulations in this study reveal initial lipids raft formation near the catalytic site of gamma-secretase as well as changes in dynamic behavior of gamma-secretase once interacting with APP. The results suggest a precursor of the APP binding mode and hint at conformational changes of gamma-secretase in the nicastrin (NCT) domain upon APP binding. (C) 2017 Elsevier Inc. All rights reserved.