id_1036. MECHANISTIC INSIGHTS INTO GAMMA-SECRETASE CLEAVAGE OF AMYLOID-Β PEPTIDES VIA STEERED MOLECULAR DYNAMICS SIMULATIONS
Emilia Wójcik1,2, Urszula Orzeł1,3, Paweł Pasznik1, Sławomir Filipek1
1 Section of Inorganic and Analytical Chemistry, Faculty of Chemistry, Biological and Chemical Research Centre, University of Warsaw, Warsaw, Poland
2 Inter-faculty Individual Studies in Mathematics and Natural Sciences, University of Warsaw, Warsaw, Poland
3 PhD Programme in Biosciences, Department of Life Sciences, University of Coimbra, Coimbra, Portugal
INTRODUCTION: Gamma-secretase (GS) is a multi-subunit intramembrane aspartyl protease that cleaves over 150 type I transmembrane proteins. Its catalytic core is formed by Presenilin. Among its substrates, the most extensively studied is the Amyloid precursor protein (APP). GS-mediated processing of APP generates amyloid-β peptides, predominantly Aβ40 and Aβ42. An increased Aβ42:Aβ40 ratio is a hallmark of Alzheimer's disease (AD), reflecting a shift toward the longer, more aggregation-prone Aβ42 species.
AIM(S): To develop an accessible computational model of GS proteolysis that enables mechanistic investigation of substrate cleavage and identification of crucial interactions stabilizing the substrate during catalysis.
METHOD(S): We performed Steered Molecular Dynamics (SMD) simulations using our GS-SMD server. Simulations were conducted in an implicit membrane and solvent environment to substantially reduce computational cost while preserving essential protein–substrate interactions.
RESULTS: Our simulations identified key interactions and specific residues within Presenilin that stabilize the substrate during cleavage. These interaction networks appear critical for maintaining substrate positioning within the catalytic site.
CONCLUSIONS: We established a computationally efficient model that provides mechanistically meaningful insight into GS-mediated proteolysis. Importantly, several identified stabilizing residues in presenilin correspond to sites known to harbor pathogenic mutations in familial AD, supporting the biological relevance of our approach.
FINANCIAL SUPPORT: This research was conducted without external financial support.