Assigning the protonation states of the key aspartates in β-Secretase using QM/MM X-ray structure refinement.

ABSTRACT: β-Secretase, a.k.a. β-APP cleaving enzyme (BACE), is an aspartyl protease that has been implicated as a key target in the pathogenesis of Alzheimer's disease (AD). The identification of the protonation states of the key aspartates in β-secretase is of great interest both in understanding the reaction mechanism and in guiding the design of drugs against AD. However, the resolutions of currently available crystal structures for BACE are not sufficient to determine the hydrogen atom locations. We have assigned the protonation states of the key aspartates using a novel method, QM/MM X-ray refinement. In our approach, an energy function is introduced to the refinement where the atoms in the active site are modeled by quantum mechanics (QM) and the other atoms are represented by molecular mechan

SUBMITTER: Yu N 

PROVIDER: S-EPMC2600719 | biostudies-literature | 2006

REPOSITORIES: biostudies-literature