ADAM10 and BACE1 are two critical secretases in the pathway of Amyloid Beta production, the fibrillization of which can lead to Alzheimer’s Disease. The cleavage activity of ADAM10 and BACE1 is dependent on their cellular co-localization with Amyloid Precursor Protein. Experimentally it is challenging to determine the specific lipid environment surrounding these proteins, which determines both protein-protein co-localization and structure. Approaching this goal computationally requires determination of a robust transmembrane congener of ADAM10 and BACE1. To determine these congeners, we have performed Replica Exchange Molecular Dynamics of truncated ADAM10 and BACE1 sequences to obtain a minimal sequence which can reproduce the dynamics of longer sequences with minimal losses to accuracy. We explored conformational ensemble of these protein congeners in membranes of varying thickness. Rigid body motions, secondary structure, alpha-carbon positions, dihedrals, and depths of insertion to membranes were considered to determine optimal congeners of ADAM10 and BACE1. Using these ADAM10 and BACE1 congeners, future computational modeling of protein partitioning in varieties of complex lipid environments can be explored to develop a kinetically-detailed picture of activation or inactivation of Amyloid Beta production pathways.

Probing the transmembrane domain structure of BACE1 and ADAM10

Macromolecular Chemistry: The Second Century

[Author Benefits](https://scimeetings.acs.org/?utm_source=pubs_content_marketing&utm_medium=website&utm_campaign=0320_MCF_NPI_Launch_Spring_Homepage&ref=pubs_content_marketing)

[How to use SciMeetings](https://storage.googleapis.com/dl.morressier.com/acs/SciMeetings-ACSSpring2020-HowToGuide_M3020-Final.pdf)

[Frequently Asked Questions](https://storage.googleapis.com/dl.morressier.com/acs/SciMtng_ACSNMSp2020_FAQ_M3120_Final.pdf)

ACS Spring 2020 National Meeting & Expo

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.