GS-SMD

GS-SMD performs steered molecular dynamics (SMD) simulations to investigate peptide substrates in the active site of the γ-secretase complex, probing substrate cleavage and unfolding relevant to Alzheimer's disease across over 170 known γ-secretase substrates.

Key Features:

• Substrate Threading: Threading of peptide sequences into an established γ-secretase structure to generate starting conformations for simulations.
• Implicit Water-Membrane Environment: Simulations run in an implicit water-membrane environment to reduce computational cost with typical runtimes of 2–6 hours per job.
• Steered Molecular Dynamics (SMD): Constant-velocity SMD enabling directed manipulation of substrate components in arbitrary directions to probe mechanical unfolding and cleavage.
• Mutation Analysis: Introduction of specific mutations into both substrate and γ-secretase to assess effects on substrate processing and enzyme function.
• Trajectory Visualization and Interaction Frequency Analysis: Visualization of simulation trajectories and computation of interaction frequency to compare and analyze multiple simulations.

Scientific Applications:

• Mechanistic studies of cleavage and unfolding: Investigation of peptide substrate cleavage and unfolding dynamics within the γ-secretase active site.
• Mutation impact analysis: Assessment of how specific mutations in substrate or γ-secretase alter substrate processing and enzyme activity.
• Alzheimer's disease research: Generation of mechanistic insights relevant to modulating γ-secretase activity to mitigate amyloidogenic product overproduction in Alzheimer's disease.

Methodology:

Threading peptide sequences into the γ-secretase structure followed by constant-velocity SMD simulations in an implicit water-membrane environment, with mutation modeling and interaction frequency analysis applied to simulation trajectories.