Alzheimer's disease, a devastating neurodegenerative disorder resulting in memory loss and eventually dementia, is characterized by the formation of insoluble amyloid plaques in the vascular and hippocampal areas of the brain. Site-specific hydrolytic catalysis of β-secretase, or BACE-1, is responsible for production of these oligomerative amyloid β-peptides (Aβ-peptides). Since BACE-1 catalyzes the initial site specific hydrolysis step in Aβ-peptide formation, understanding the mechanism of the BACE-1 catalytic site is key to eventually designing therapeutics to prevent the onset of Alzheimer's disease. The activity of BACE-1 is known to rely on water mediated transport of protons from aspartyl dyad to substrate in a pH dependent process. As a result of this pH dependent nature, conventional molecular dynamics (cMD) simulations, which assume constant protonation states, have been unsuccessfully applied to the investigation of BACE-1. In particular, ΔG<sub>binding</sub> of inhibitor binding to BACE-1 have been found to be incorrect by as large as 8 kcal/mol. This is even more significant when considering that a nanomolar binding inhibitor only has a ΔG<sub>binding </sub>of -12 kcal/mol. We have applied constant pH molecular dynamics with replica exchange (CpH-REMD) newly implemented on graphics processors (GPUs) in the AMBER molecular dynamics software package in order to properly investigate the BACE-1 mechanism and develop novel inhibitors.

Constant pH-replica exchange on graphics processors applied to beta-secretase 1 inhibitor design

251st National Meeting (2016)

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