TY - JOUR KW - Computer Simulation KW - Hydrogen Bonding KW - Kinetics KW - Models, Molecular KW - Protein Structure, Secondary KW - Crystallography, X-Ray KW - Humans KW - Oligopeptides KW - Protein Conformation KW - Amino Acid Sequence KW - Molecular Sequence Data KW - Aspartic Acid Endopeptidases KW - Binding Sites KW - Water KW - Amyloid Precursor Protein Secretases KW - Endopeptidases KW - Alzheimer Disease KW - Tyrosine KW - Temperature KW - Enzyme Inhibitors KW - Substrate Specificity KW - Amyloid beta-Protein Precursor KW - Asparagine KW - Catalysis KW - Protons KW - Serine AU - A. A. Gorfe AU - A. Caflisch AB -

The aspartic protease β-secretase (BACE) cleaves the amyloid precursor protein into a 42 residue β-peptide, which is the principal biochemical marker of Alzheimer's disease. Multiple explicit-water molecular dynamics simulations of the apo and inhibitor bound structures of BACE indicate that both open- and closed-flap conformations are accessible at room temperature and should be taken into account for inhibitor design. Correlated motion is observed within each of the two lobes of BACE, as well as for the interfacial region. A self-inhibited conformation with the side chain of Tyr71 occupying the S1 pocket is present in some of the unbound simulations. The reversible loss of the side chain hydrogen bond between the catalytic Asp32 and Ser35, due to the concomitant reorientation of the Ser35 hydroxyl group and a water molecule conserved in pepsin-like enzymes, provides further evidence for the suggestion that Ser35 assists in proton acceptance and release by Asp32 during catalysis.

BT - Structure C1 - 0071 DA - 2005 Oct DO - 10.1016/j.str.2005.06.015 IS - 10 J2 - Structure LA - eng M3 - Research Article N2 -

The aspartic protease β-secretase (BACE) cleaves the amyloid precursor protein into a 42 residue β-peptide, which is the principal biochemical marker of Alzheimer's disease. Multiple explicit-water molecular dynamics simulations of the apo and inhibitor bound structures of BACE indicate that both open- and closed-flap conformations are accessible at room temperature and should be taken into account for inhibitor design. Correlated motion is observed within each of the two lobes of BACE, as well as for the interfacial region. A self-inhibited conformation with the side chain of Tyr71 occupying the S1 pocket is present in some of the unbound simulations. The reversible loss of the side chain hydrogen bond between the catalytic Asp32 and Ser35, due to the concomitant reorientation of the Ser35 hydroxyl group and a water molecule conserved in pepsin-like enzymes, provides further evidence for the suggestion that Ser35 assists in proton acceptance and release by Asp32 during catalysis.

PY - 2005 SP - 1487 EP - 1498 T2 - Structure TI - Functional plasticity in the substrate binding site of beta-secretase VL - 13 SN - 0969-2126 ER -