Structure Prediction of the Transmembrane Region of Alpha- and Beta- Secretases using Replica-Exchange Molecular Dynamics Simulations, and the Interaction between Amyloid Precursor Protein and Them

Abstract

Alzheimer’s disease (AD) is known as one of dementia, and the number of patients has been increasing around the world. Amyloid Precursor Protein (APP) is one of the key membrane proteins in the pathogenesis of AD according to the amyloid hypothesis. in the early stage of Alzheimer’s disease, APP is cleaved by beta- and gamma-secretases in the lipid raft environments, and amyloid-beta peptides are produced. The amyloid-beta peptides are aggregated with each other and the senile plaques are produced. in a normal situation, the APP is usually cleaved by alpha-secretase in non-raft environments. This process is not related to the process of AD. Thus, the interactions among APP, alpha- and beta- secretases are very important in the progressing of the disease. However, the tertiary structure of the transmembrane domain of alpha- and beta- secretases have not been solved experimentally. Therefore, currently it is difficult to understand the interaction among APP, alpha- and beta- secretases in the biological membrane.To understand the interaction among APP, alpha- and beta- secretases, we performed the structure prediction of the transmembrane domain of alpha- and beta- secretases using the Replica-exchange molecular dynamics simulations (REMD). The structure of the transmembrane domain of alpha-secretase has one long transmembrane helix with the bending outside of the membrane, and that of beta-secretase has two domains with a bend at the proline in the membrane. We also carried out the Coarse-Grained molecular dynamics simulations of the transmembrane domain of alpha/beta- secretase and the transmembrane domain of APP complex system in the biological membrane environments. in the hetero-dimerization of beta-secretase and APP, sphingolipids and cholesterols support the interaction between secretases and APP.